Research

20 pages, 2010 KiB

Open AccessArticle

The Role of ZEB2 in Human CD8 T Lymphocytes: Clinical and Cellular Immune Profiling in Mowat–Wilson Syndrome

by Katie Frith, C. Mee Ling Munier, Lucy Hastings, David Mowat, Meredith Wilson, Nabila Seddiki, Rebecca Macintosh, Anthony D. Kelleher, Paul Gray and John James Zaunders

Int. J. Mol. Sci. 2021, 22(10), 5324; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105324 - 18 May 2021

Cited by 3 | Viewed by 2688

Abstract

The Zeb2 gene encodes a transcription factor (ZEB2) that acts as an important immune mediator in mice, where it is expressed in early-activated effector CD8 T cells, and limits effector differentiation. Zeb2 homozygous knockout mice have deficits in CD8 T cells and NK [...] Read more.

The Zeb2 gene encodes a transcription factor (ZEB2) that acts as an important immune mediator in mice, where it is expressed in early-activated effector CD8 T cells, and limits effector differentiation. Zeb2 homozygous knockout mice have deficits in CD8 T cells and NK cells. Mowat–Wilson syndrome (MWS) is a rare genetic disease resulting from heterozygous mutations in ZEB2 causing disease by haploinsufficiency. Whether ZEB2 exhibits similar expression patterns in human CD8 T cells is unknown, and MWS patients have not been comprehensively studied to identify changes in CD8 lymphocytes and NK cells, or manifestations of immunodeficiency. By using transcriptomic assessment, we demonstrated that ZEB2 is expressed in early-activated effector CD8 T cells of healthy human volunteers following vaccinia inoculation and found evidence of a role for TGFß-1/SMAD signaling in these cells. A broad immunological assessment of six genetically diagnosed MWS patients identified two patients with a history of recurrent sinopulmonary infections, one of whom had recurrent oral candidiasis, one with lymphopenia, two with thrombocytopenia and three with detectable anti-nuclear antibodies. Immunoglobulin levels, including functional antibody responses to protein and polysaccharide vaccination, were normal. The MWS patients had a significantly lower CD8 T cell subset as % of lymphocytes, compared to healthy controls (median 16.4% vs. 25%, p = 0.0048), and resulting increased CD4:CD8 ratio (2.6 vs. 1.8; p = 0.038). CD8 T cells responded normally to mitogen stimulation in vitro and memory CD8 T cells exhibited normal proportions of subsets with important tissue-specific homing markers and cytotoxic effector molecules. There was a trend towards a decrease in the CD8 T effector memory subset (3.3% vs. 5.9%; p = 0.19). NK cell subsets were normal. This is the first evidence that ZEB2 is expressed in early-activated human effector CD8 T cells, and that haploinsufficiency of ZEB2 in MWS patients had a slight effect on immune function, skewing T cells away from CD8 differentiation. To date there is insufficient evidence to support an immunodeficiency occurring in MWS patients. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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17 pages, 5410 KiB

Open AccessArticle

In Vitro Suppression of T Cell Proliferation Is a Conserved Function of Primary and Immortalized Human Cancer-Associated Fibroblasts

by Mohammed H. Abuwarwar, Alfie T. Baker, Jeffrey Harding, Natalie L. Payne, Andras Nagy, Konstantin Knoblich and Anne L. Fletcher

Int. J. Mol. Sci. 2021, 22(4), 1827; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041827 - 12 Feb 2021

Cited by 10 | Viewed by 3647

Abstract

T cell immunotherapy is now a mainstay therapy for several blood-borne cancers as well as metastatic melanoma. Unfortunately, many epithelial tumors respond poorly to immunotherapy, and the reasons for this are not well understood. Cancer-associated fibroblasts (CAFs) are the most frequent non-neoplastic cell [...] Read more.

T cell immunotherapy is now a mainstay therapy for several blood-borne cancers as well as metastatic melanoma. Unfortunately, many epithelial tumors respond poorly to immunotherapy, and the reasons for this are not well understood. Cancer-associated fibroblasts (CAFs) are the most frequent non-neoplastic cell type in most solid tumors, and they are emerging as a key player in immunotherapy resistance. A range of immortalized CAF lines will be essential tools that will allow us to understand immune responses against cancer and develop novel strategies for cancer immunotherapy. To study the effect of CAFs on T cell proliferation, we created and characterized a number of novel immortalized human CAFs lines (Im-CAFs) from human breast, colon, and pancreatic carcinomas. Im-CAFs shared similar phenotypes, matrix remodeling and contraction capabilities, and growth and migration rates compared to the primary CAFs. Using primary isolates from breast carcinoma, colorectal carcinoma, and pancreatic ductal adenocarcinoma, we report that CAFs across major tumor types are able to potently suppress T cell proliferation in vitro. Im-CAFs retained this property. Im-CAFs are a key tool that will provide important insights into the mechanisms of CAF-mediated T cell suppression through techniques such as CRISPR-Cas9 modification, molecular screens, and pipeline drug testing. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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16 pages, 7261 KiB

Open AccessArticle

Genetic Bias, Diversity Indices, Physiochemical Properties and CDR3 Motifs Divide Auto-Reactive from Allo-Reactive T-Cell Repertoires

by Oscar L. Haigh, Emma J. Grant, Thi H. O. Nguyen, Katherine Kedzierska, Matt A. Field and John J. Miles

Int. J. Mol. Sci. 2021, 22(4), 1625; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041625 - 05 Feb 2021

Cited by 2 | Viewed by 2749

Abstract

The distinct properties of allo-reactive T-cell repertoires are not well understood. To investigate whether auto-reactive and allo-reactive T-cell repertoires encoded distinct properties, we used dextramer enumeration, enrichment, single-cell T-cell receptor (TCR) sequencing and multiparameter analysis. We found auto-reactive and allo-reactive T-cells differed in [...] Read more.

The distinct properties of allo-reactive T-cell repertoires are not well understood. To investigate whether auto-reactive and allo-reactive T-cell repertoires encoded distinct properties, we used dextramer enumeration, enrichment, single-cell T-cell receptor (TCR) sequencing and multiparameter analysis. We found auto-reactive and allo-reactive T-cells differed in mean ex vivo frequency which was antigen dependent. Allo-reactive T-cells showed clear differences in TCR architecture, with enriched usage of specific T-cell receptor variable (TRBJ) genes and broader use of T-cell receptor variable joining (TRBJ) genes. Auto-reactive T-cell repertoires exhibited complementary determining regions three (CDR3) lengths using a Gaussian distribution whereas allo-reactive T-cell repertoires exhibited distorted patterns in CDR3 length. CDR3 loops from allo-reactive T-cells showed distinct physical-chemical properties, tending to encode loops that were more acidic in charge. Allo-reactive T-cell repertoires differed in diversity metrics, tending to show increased overall diversity and increased homogeneity between repertoires. Motif analysis of CDR3 loops showed allo-reactive T-cell repertoires differed in motif preference which included broader motif use. Collectively, these data conclude that allo-reactive T-cell repertoires are indeed different to auto-reactive repertoires and provide tangible metrics for further investigations and validation. Given that the antigens studied here are overexpressed on multiple cancers and that allo-reactive TCRs often show increased ligand affinity, this new TCR bank also has translational potential for adoptive cell therapy, soluble TCR-based therapy and rational TCR design. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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28 pages, 7122 KiB

Open AccessArticle

CD73⁺ CD127^high Long-Term Memory CD4 T Cells Are Highly Proliferative in Response to Recall Antigens and Are Early Targets in HIV-1 Infection

by Nabila Seddiki, John Zaunders, Chan Phetsouphanh, Vedran Brezar, Yin Xu, Helen M. McGuire, Michelle Bailey, Kristin McBride, Will Hey-Cunningham, Cynthia Mee Ling Munier, Laura Cook, Stephen Kent, Andrew Lloyd, Barbara Cameron, Barbara Fazekas de St Groth, Kersten Koelsch, Mark Danta, Hakim Hocini, Yves Levy and Anthony D. Kelleher

Int. J. Mol. Sci. 2021, 22(2), 912; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020912 - 18 Jan 2021

Cited by 2 | Viewed by 3248

Abstract

HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the [...] Read more.

HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5–10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6–6.4%; p = 0.002); and in chronic HIV-1 infection to 1.9% (IQR: 1.1–3%; p < 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and β7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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14 pages, 2213 KiB

Open AccessArticle

CD85k Contributes to Regulatory T Cell Function in Chronic Viral Infections

by Anna Estrada Brull, Felix Rost, Josua Oderbolz, Florian R. Kirchner, Salomé Leibundgut-Landmann, Annette Oxenius and Nicole Joller

Int. J. Mol. Sci. 2021, 22(1), 31; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010031 - 22 Dec 2020

Cited by 3 | Viewed by 3038

Abstract

Regulatory T cells (Tregs) prevent excessive immune responses and limit immune pathology upon infections. To fulfill this role in different immune environments elicited by different types of pathogens, Tregs undergo functional specialization into distinct subsets. During acute type 1 immune responses, type 1 [...] Read more.

Regulatory T cells (Tregs) prevent excessive immune responses and limit immune pathology upon infections. To fulfill this role in different immune environments elicited by different types of pathogens, Tregs undergo functional specialization into distinct subsets. During acute type 1 immune responses, type 1 Tregs are induced and recruited to the site of ongoing Th1 responses to efficiently control Th1 responses. However, whether a similar specialization process also takes place following chronic infections is still unknown. In this study, we investigated Treg specialization in persistent viral infections using lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV) infection as models for chronic and latent infections, respectively. We identify CD85k as a Th1-specific co-inhibitory receptor with sustained expression in persistent viral infections and show that recombinant CD85k inhibits LCMV-specific effector T cells. Furthermore, expression of the CD85k ligand ALCAM is induced on LCMV-specific and exhausted T cells during chronic LCMV infection. Finally, we demonstrate that type 1 Tregs arising during chronic LCMV infection suppress Th1 effector cells in an ALCAM-dependent manner. These results extend the current knowledge of Treg specialization from acute to persistent viral infections and reveal an important functional role of CD85k in Treg-mediated suppression of type 1 immunity. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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12 pages, 1613 KiB

Open AccessCommunication

Human Thymic CD10⁺ PD-1⁺ Intraepithelial Lymphocyte Precursors Acquire Interleukin-15 Responsiveness at the CD1a^– CD95⁺ CD28^– CCR7^– Developmental Stage

by Lore Billiet, Glenn Goetgeluk, Sarah Bonte, Stijn De Munter, Laurenz De Cock, Melissa Pille, Joline Ingels, Hanne Jansen, Karin Weening, Filip Van Nieuwerburgh, Tessa Kerre, Tom Taghon, Georges Leclercq and Bart Vandekerckhove

Int. J. Mol. Sci. 2020, 21(22), 8785; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228785 - 20 Nov 2020

Cited by 6 | Viewed by 2362

Abstract

Human thymic CD8αα⁺ CD10⁺ PD-1⁺ αβ T cells selected through early agonist selection have been proposed as the putative thymic precursors of the human CD8αα⁺ intestinal intraepithelial lymphocytes (IELs). However, the progeny of these thymic precursor cells in human [...] Read more.

Human thymic CD8αα⁺ CD10⁺ PD-1⁺ αβ T cells selected through early agonist selection have been proposed as the putative thymic precursors of the human CD8αα⁺ intestinal intraepithelial lymphocytes (IELs). However, the progeny of these thymic precursor cells in human blood or tissues has not yet been characterized. Here, we studied the phenotypical and transcriptional differentiation of the thymic IEL precursor (IELp) lineage upon in vitro exposure to cytokines prominent in the peripheral tissues such as interleukin-15 (IL-15) and the inflammatory cytokines interleukin-12 (IL-12) and interleukin-18 (IL-18). We showed that only the CD1a⁻ fraction of the CD10⁺ PD-1⁺ IELp population was able to proliferate with IL-15, suggesting that this subset had acquired functionality. These cells downregulated PD-1 expression and completely lost CD10 expression, whereas other surface markers such as CD95 and CXCR3 remained highly expressed. RNA-seq analysis of the IL-15-cultured cells clearly showed induction of innate-like and effector genes. Induction of the cytotoxic machinery by the CD10⁺ PD-1⁺ population was acquired in the presence of IL-15 and was further augmented by inflammatory cytokines. Our data suggest that only the CD1a⁻ CD10⁺ PD-1⁺ population exits the thymus and survives in the periphery. Furthermore, PD-1 and CD10 expression is not an intrinsic property of this lineage, but rather characterizes a transient stage in differentiation. CD95 and CXCR3 expression combined with the absence of CD28, CCR7, and CD6 expression might be more powerful markers to define this lineage in the periphery. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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19 pages, 2642 KiB

Open AccessArticle

Impact of HLA-DR Antigen Binding Cleft Rigidity on T Cell Recognition

by Christopher Szeto, Joseph I. Bloom, Hannah Sloane, Christian A. Lobos, James Fodor, Dhilshan Jayasinghe, Demetra S. M. Chatzileontiadou, Emma J. Grant, Ashley M. Buckle and Stephanie Gras

Int. J. Mol. Sci. 2020, 21(19), 7081; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197081 - 25 Sep 2020

Cited by 7 | Viewed by 3809

Abstract

The interaction between T cell receptor (TCR) and peptide (p)-Human Leukocyte Antigen (HLA) complexes is the critical first step in determining T cell responses. X-ray crystallographic studies of pHLA in TCR-bound and free states provide a structural perspective that can help understand T [...] Read more.

The interaction between T cell receptor (TCR) and peptide (p)-Human Leukocyte Antigen (HLA) complexes is the critical first step in determining T cell responses. X-ray crystallographic studies of pHLA in TCR-bound and free states provide a structural perspective that can help understand T cell activation. These structures represent a static “snapshot”, yet the nature of pHLAs and their interactions with TCRs are highly dynamic. This has been demonstrated for HLA class I molecules with in silico techniques showing that some interactions, thought to stabilise pHLA-I, are only transient and prone to high flexibility. Here, we investigated the dynamics of HLA class II molecules by focusing on three allomorphs (HLA-DR1, -DR11 and -DR15) that are able to present the same epitope and activate CD4+ T cells. A single TCR (F24) has been shown to recognise all three HLA-DR molecules, albeit with different affinities. Using molecular dynamics and crystallographic ensemble refinement, we investigate the molecular basis of these different affinities and uncover hidden roles for HLA polymorphic residues. These polymorphisms were responsible for the widening of the antigen binding cleft and disruption of pHLA-TCR interactions, underpinning the hierarchy of F24 TCR binding affinity, and ultimately T cell activation. We expanded this approach to all available pHLA-DR structures and discovered that all HLA-DR molecules were inherently rigid. Together with in vitro protein stability and peptide affinity measurements, our results suggest that HLA-DR1 possesses inherently high protein stability, and low HLA-DM susceptibility. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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11 pages, 1428 KiB

Open AccessArticle

Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner

by Tiago Carvalheiro, Carlos Rafael-Vidal, Beatriz Malvar-Fernandez, Ana P. Lopes, Jose M. Pego-Reigosa, Timothy R. D. J. Radstake and Samuel Garcia

Int. J. Mol. Sci. 2020, 21(18), 6965; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186965 - 22 Sep 2020

Cited by 18 | Viewed by 3085

Abstract

Semaphorin (Sema)4A is a transmembrane glycoprotein that is elevated in several autoimmune diseases such as systemic sclerosis, rheumatoid arthritis and multiple sclerosis. Sema4A has a key role in the regulation of Thelper Th1 and Th2 differentiation and we recently demonstrated that CD4⁺ [...] Read more.

Semaphorin (Sema)4A is a transmembrane glycoprotein that is elevated in several autoimmune diseases such as systemic sclerosis, rheumatoid arthritis and multiple sclerosis. Sema4A has a key role in the regulation of Thelper Th1 and Th2 differentiation and we recently demonstrated that CD4⁺ T cell activation induces the expression of Sema4A. However, the autocrine role of Sema4A on Th cell differentiation remains unknown. Naïve Th cells from healthy controls were cell sorted and differentiated into Th1, Th2 and Th17 in the presence or absence of a neutralizing antibody against the Sema4A receptor PlexinD1. Gene expression was determined by quantitative PCR and protein expression by ELISA and flow cytometry. We found that the expression of Sema4A is induced during Th1, Th2 and Th17 differentiation. PlexinD1 neutralization induced the differentiation of Th1 cells, while reduced the Th2 and Th17 skewing. These effects were associated with an upregulation of the transcription factor T-bet by Th1 cells, and to downregulation of GATA3 and RORγt in Th2 cells and Th17 cells, respectively. Finally, PlexinD1 neutralization regulates the systemic sclerosis patients serum-induced cytokine production by CD4⁺ T cells. Therefore, the autocrine Sema4A-PlexinD1 signaling acts as a negative regulator of Th1 skewing but is a key mediator on Th2 and Th17 differentiation, suggesting that dysregulation of this axis might be implicated in the pathogenesis of CD4⁺ T cell-mediated diseases. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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13 pages, 3188 KiB

Open AccessArticle

Investigation of Cytotoxic T Lymphocyte Function during Allorejection in the Anterior Chamber of the Eye

by Hsin-Fang Chang, Marie-Louise Wirkner, Elmar Krause and Jens Rettig

Int. J. Mol. Sci. 2020, 21(13), 4660; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134660 - 30 Jun 2020

Cited by 2 | Viewed by 2574

Abstract

Cytotoxic T lymphocytes (CTL) are an essential part of our immune system by killing infected and malignant cells. To fully understand this process, it is necessary to study CTL function in the physiological setting of a living organism to account for their interplay [...] Read more.

Cytotoxic T lymphocytes (CTL) are an essential part of our immune system by killing infected and malignant cells. To fully understand this process, it is necessary to study CTL function in the physiological setting of a living organism to account for their interplay with other immune cells like CD4⁺ T helper cells and macrophages. The anterior chamber of the eye (ACE), originally developed for diabetes research, is ideally suited for non-invasive and longitudinal in vivo imaging. We take advantage of the ACE window to observe immune responses, particularly allorejection of islets of Langerhans cells by CTLs. We follow the onset of the rejection after vascularization on islets until the end of the rejection process for about a month by repetitive two-photon microscopy. We find that CTLs show reduced migration on allogeneic islets in vivo compared to in vitro data, indicating CTL activation. Interestingly, the temporal infiltration pattern of T cells during rejection is precisely regulated, showing enrichment of CD4⁺ T helper cells on the islets before arrival of CD8⁺ CTLs. The adaptation of the ACE to immune responses enables the examination of the mechanism and regulation of CTL-mediated killing in vivo and to further investigate the killing in gene-deficient mice that resemble severe human immune diseases. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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25 pages, 6464 KiB

Open AccessArticle

Clustering of the ζ-Chain Can Initiate T Cell Receptor Signaling

by Yuanqing Ma, Yean J. Lim, Aleš Benda, Jieqiong Lou, Jesse Goyette and Katharina Gaus

Int. J. Mol. Sci. 2020, 21(10), 3498; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103498 - 15 May 2020

Cited by 18 | Viewed by 4008

Abstract

T cell activation is initiated when ligand binding to the T cell receptor (TCR) triggers intracellular phosphorylation of the TCR-CD3 complex. However, it remains unknown how biophysical properties of TCR engagement result in biochemical phosphorylation events. Here, we constructed an optogenetic tool that [...] Read more.

T cell activation is initiated when ligand binding to the T cell receptor (TCR) triggers intracellular phosphorylation of the TCR-CD3 complex. However, it remains unknown how biophysical properties of TCR engagement result in biochemical phosphorylation events. Here, we constructed an optogenetic tool that induces spatial clustering of ζ-chain in a light controlled manner. We showed that spatial clustering of the ζ-chain intracellular tail alone was sufficient to initialize T cell triggering including phosphorylation of ζ-chain, Zap70, PLCγ, ERK and initiated Ca²⁺ flux. In reconstituted COS-7 cells, only Lck expression was required to initiate ζ-chain phosphorylation upon ζ-chain clustering, which leads to the recruitment of tandem SH2 domain of Zap70 from cell cytosol to the newly formed ζ-chain clusters at the plasma membrane. Taken together, our data demonstrated the biophysical relevance of receptor clustering in TCR signaling. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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Review

Jump to: Research, Other

17 pages, 1148 KiB

Open AccessReview

Investigating T Cell Immunity in Cancer: Achievements and Prospects

by Zhen Zeng, Hui Yi Chew, Jazmina G. Cruz, Graham R. Leggatt and James W. Wells

Int. J. Mol. Sci. 2021, 22(6), 2907; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062907 - 12 Mar 2021

Cited by 11 | Viewed by 2941

Abstract

T cells play a key role in tumour surveillance, both identifying and eliminating transformed cells. However, as tumours become established they form their own suppressive microenvironments capable of shutting down T cell function, and allowing tumours to persist and grow. To further understand [...] Read more.

T cells play a key role in tumour surveillance, both identifying and eliminating transformed cells. However, as tumours become established they form their own suppressive microenvironments capable of shutting down T cell function, and allowing tumours to persist and grow. To further understand the tumour microenvironment, including the interplay between different immune cells and their role in anti-tumour immune responses, a number of studies from mouse models to clinical trials have been performed. In this review, we examine mechanisms utilized by tumour cells to reduce their visibility to CD8⁺ Cytotoxic T lymphocytes (CTL), as well as therapeutic strategies trialled to overcome these tumour-evasion mechanisms. Next, we summarize recent advances in approaches to enhance CAR T cell activity and persistence over the past 10 years, including bispecific CAR T cell design and early evidence of efficacy. Lastly, we examine mechanisms of T cell infiltration and tumour regression, and discuss the strengths and weaknesses of different strategies to investigate T cell function in murine tumour models. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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15 pages, 1875 KiB

Open AccessReview

Novel Molecular Insights into Human Lipid-Mediated T Cell Immunity

by Adam Shahine, Marcin Wegrecki and Jérôme Le Nours

Int. J. Mol. Sci. 2021, 22(5), 2617; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052617 - 05 Mar 2021

Cited by 3 | Viewed by 2823

Abstract

T cells represent a critical arm of our immune defense against pathogens. Over the past two decades, considerable inroads have been made in understanding the fundamental principles underpinning the molecular presentation of peptide-based antigens by the Major Histocompatibility Complex molecules (MHC-I and II), [...] Read more.

T cells represent a critical arm of our immune defense against pathogens. Over the past two decades, considerable inroads have been made in understanding the fundamental principles underpinning the molecular presentation of peptide-based antigens by the Major Histocompatibility Complex molecules (MHC-I and II), and their molecular recognition by specialized subsets of T cells. However, some T cells can recognize lipid-based antigens presented by MHC-I-like molecules that belong to the Cluster of Differentiation 1 (CD1) family. Here, we will review the advances that have been made in the last five years to understand the molecular mechanisms orchestrating the presentation of novel endogenous and exogenous lipid-based antigens by the CD1 glycoproteins and their recognition by specific populations of CD1-reactive T cells. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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11 pages, 695 KiB

Open AccessReview

Drug Reaction with Eosinophilia and Systemic Symptoms: A Complex Interplay between Drug, T Cells, and Herpesviridae

by Luckshman Ganeshanandan and Michaela Lucas

Int. J. Mol. Sci. 2021, 22(3), 1127; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031127 - 23 Jan 2021

Cited by 7 | Viewed by 3167

Abstract

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, also known as drug induced hypersensitivity (DiHS) syndrome is a severe delayed hypersensitivity reaction with potentially fatal consequences. Whilst recognised as T cell-mediated, our understanding of the immunopathogenesis of this syndrome remains incomplete. Here, [...] Read more.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, also known as drug induced hypersensitivity (DiHS) syndrome is a severe delayed hypersensitivity reaction with potentially fatal consequences. Whilst recognised as T cell-mediated, our understanding of the immunopathogenesis of this syndrome remains incomplete. Here, we discuss models of DRESS, including the role of human leukocyte antigen (HLA) and how observations derived from new molecular techniques adopted in key studies have informed our mechanism-based understanding of the central role of Herpesviridae reactivation and heterologous immunity in these disorders. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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23 pages, 667 KiB

Open AccessReview

Role of CD4+ T Cells in the Control of Viral Infections: Recent Advances and Open Questions

by Jérôme Kervevan and Lisa A. Chakrabarti

Int. J. Mol. Sci. 2021, 22(2), 523; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020523 - 07 Jan 2021

Cited by 27 | Viewed by 6433

Abstract

CD4+ T cells orchestrate adaptive immune responses through their capacity to recruit and provide help to multiple immune effectors, in addition to exerting direct effector functions. CD4+ T cells are increasingly recognized as playing an essential role in the control of chronic viral [...] Read more.

CD4+ T cells orchestrate adaptive immune responses through their capacity to recruit and provide help to multiple immune effectors, in addition to exerting direct effector functions. CD4+ T cells are increasingly recognized as playing an essential role in the control of chronic viral infections. In this review, we present recent advances in understanding the nature of CD4+ T cell help provided to antiviral effectors. Drawing from our studies of natural human immunodeficiency virus (HIV) control, we then focus on the role of high-affinity T cell receptor (TCR) clonotypes in mediating antiviral CD4+ T cell responses. Last, we discuss the role of TCR affinity in determining CD4+ T cell differentiation, reviewing the at times divergent studies associating TCR signal strength to the choice of a T helper 1 (Th1) or a T follicular helper (Tfh) cell fate. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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27 pages, 3694 KiB

Open AccessReview

The Many Faces of CD4⁺ T Cells: Immunological and Structural Characteristics

by Demetra S. M. Chatzileontiadou, Hannah Sloane, Andrea T. Nguyen, Stephanie Gras and Emma J. Grant

Int. J. Mol. Sci. 2021, 22(1), 73; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010073 - 23 Dec 2020

Cited by 47 | Viewed by 7570

Abstract

As a major arm of the cellular immune response, CD4⁺ T cells are important in the control and clearance of infections. Primarily described as helpers, CD4⁺ T cells play an integral role in the development and activation of B cells and [...] Read more.

As a major arm of the cellular immune response, CD4⁺ T cells are important in the control and clearance of infections. Primarily described as helpers, CD4⁺ T cells play an integral role in the development and activation of B cells and CD8⁺ T cells. CD4⁺ T cells are incredibly heterogeneous, and can be divided into six main lineages based on distinct profiles, namely T helper 1, 2, 17 and 22 (Th1, Th2, Th17, Th22), regulatory T cells (Treg) and T follicular helper cells (Tfh). Recent advances in structural biology have allowed for a detailed characterisation of the molecular mechanisms that drive CD4⁺ T cell recognition. In this review, we discuss the defining features of the main human CD4⁺ T cell lineages and their role in immunity, as well as their structural characteristics underlying their detection of pathogens. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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26 pages, 3551 KiB

Open AccessReview

TCR Recognition of Peptide–MHC-I: Rule Makers and Breakers

by Christopher Szeto, Christian A. Lobos, Andrea T. Nguyen and Stephanie Gras

Int. J. Mol. Sci. 2021, 22(1), 68; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010068 - 23 Dec 2020

Cited by 61 | Viewed by 9025

Abstract

T cells are a critical part of the adaptive immune system that are able to distinguish between healthy and unhealthy cells. Upon recognition of protein fragments (peptides), activated T cells will contribute to the immune response and help clear infection. The major histocompatibility [...] Read more.

T cells are a critical part of the adaptive immune system that are able to distinguish between healthy and unhealthy cells. Upon recognition of protein fragments (peptides), activated T cells will contribute to the immune response and help clear infection. The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR). This recognition event is the first step that leads to T cell activation, and in turn can dictate disease outcomes. The visualisation of TCR interaction with pMHC using structural biology has been crucial in understanding this key event, unravelling the parameters that drive this interaction and their impact on the immune response. The last five years has been the most productive within the field, wherein half of current unique TCR–pMHC-I structures to date were determined within this time. Here, we review the new insights learned from these recent TCR–pMHC-I structures and their impact on T cell activation. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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21 pages, 1922 KiB

Open AccessReview

T Lymphocytes and Testicular Immunity: A New Insight into Immune Regulation in Testes

by Jialei Gong, Qunxiong Zeng, Di Yu and Yong-Gang Duan

Int. J. Mol. Sci. 2021, 22(1), 57; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010057 - 23 Dec 2020

Cited by 31 | Viewed by 4362

Abstract

The immune privilege of the testes is necessary to prevent immune attacks to gamete-specific antigens and paternal major histocompatibility complex (MHC) antigens, allowing for normal spermatogenesis. However, infection and inflammation of the male genital tract can break the immune tolerance and represent a [...] Read more.

The immune privilege of the testes is necessary to prevent immune attacks to gamete-specific antigens and paternal major histocompatibility complex (MHC) antigens, allowing for normal spermatogenesis. However, infection and inflammation of the male genital tract can break the immune tolerance and represent a significant cause of male infertility. Different T cell subsets have been identified in mammalian testes, which may be involved in the maintenance of immune tolerance and pathogenic immune responses in testicular infection and inflammation. We reviewed the evidence in the published literature on different T subtypes (regulatory T cells, helper T cells, cytotoxic T cells, γδ T cells, and natural killer T cells) in human and animal testes that support their regulatory roles in infertility and the orchitis pathology. While many in vitro studies have indicated the regulation potential of functional T cell subsets and their possible interaction with Sertoli cells, Leydig cells, and spermatogenesis, both under physiological and pathological processes, there have been no in situ studies to date. Nevertheless, the normal distribution and function of T cell subsets are essential for the immune privilege of the testes and intact spermatogenesis, and T cell-mediated immune response drives testicular inflammation. The distinct function of different T cell subsets in testicular homeostasis and the orchitis pathology suggests a considerable potential of targeting specific T cell subsets for therapies targeting chronic orchitis and immune infertility. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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16 pages, 877 KiB

Open AccessReview

Running to Stand Still: Naive CD8⁺ T Cells Actively Maintain a Program of Quiescence

by Taylah J. Bennett, Vibha A. V. Udupa and Stephen J. Turner

Int. J. Mol. Sci. 2020, 21(24), 9773; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249773 - 21 Dec 2020

Cited by 5 | Viewed by 3762

Abstract

CD8⁺ T cells play a pivotal role in clearing intracellular pathogens and combatting tumours. Upon infection, naïve CD8⁺ T cells differentiate into effector and memory cells, and this program is underscored by large-scale and coordinated changes in the chromatin architecture and [...] Read more.

CD8⁺ T cells play a pivotal role in clearing intracellular pathogens and combatting tumours. Upon infection, naïve CD8⁺ T cells differentiate into effector and memory cells, and this program is underscored by large-scale and coordinated changes in the chromatin architecture and gene expression. Importantly, recent evidence demonstrates that the epigenetic mechanisms that regulate the capacity for rapid effector function of memory T cells are shared by innate immune cells such as natural killer (NK) cells. Thus, it appears that the crucial difference between innate and adaptive immunity is the presence of the naïve state. This important distinction raises an intriguing new hypothesis, that the naïve state was evolutionary installed to restrain a default program of effector and memory differentiation in response to antigen recognition. We argue that the hallmark of adaptive T immunity is therefore the naïve program, which actively maintains CD8⁺ T cell quiescence until receipt of appropriate activation signals. In this review, we examine the mechanistic control of naïve CD8⁺ T cell quiescence and summarise the multiple levels of restraint imposed in naïve cells in to limit spontaneous and inappropriate activation. This includes epigenetic mechanisms and transcription factor (TF) regulation of gene expression, in addition to novel inhibitory receptors, abundance of RNA, and protein degradation. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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17 pages, 669 KiB

Open AccessReview

A Cell for the Ages: Human γδ T Cells across the Lifespan

by Brandi L. Clark and Paul G. Thomas

Int. J. Mol. Sci. 2020, 21(23), 8903; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238903 - 24 Nov 2020

Cited by 21 | Viewed by 2834

Abstract

The complexity of the human immune system is exacerbated by age-related changes to immune cell functionality. Many of these age-related effects remain undescribed or driven by mechanisms that are poorly understood. γδ T cells, while considered an adaptive subset based on immunological ontogeny, [...] Read more.

The complexity of the human immune system is exacerbated by age-related changes to immune cell functionality. Many of these age-related effects remain undescribed or driven by mechanisms that are poorly understood. γδ T cells, while considered an adaptive subset based on immunological ontogeny, retain both innate-like and adaptive-like characteristics. This T cell population is small but mighty, and has been implicated in both homeostatic and disease-induced immunity within tissues and throughout the periphery. In this review, we outline what is known about the effect of age on human peripheral γδ T cells, and call attention to areas of the field where further research is needed. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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15 pages, 1319 KiB

Open AccessReview

Hiding in Plain Sight: Virtually Unrecognizable Memory Phenotype CD8⁺ T cells

by Daniel Thiele, Nicole L. La Gruta, Angela Nguyen and Tabinda Hussain

Int. J. Mol. Sci. 2020, 21(22), 8626; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228626 - 16 Nov 2020

Cited by 10 | Viewed by 5654

Abstract

Virtual memory T (T_VM) cells are a recently described population of conventional CD8⁺ T cells that, in spite of their antigen inexperience, express markers of T cell activation. T_VM cells exhibit rapid responsiveness to both antigen-specific and innate stimuli [...] Read more.

Virtual memory T (T_VM) cells are a recently described population of conventional CD8⁺ T cells that, in spite of their antigen inexperience, express markers of T cell activation. T_VM cells exhibit rapid responsiveness to both antigen-specific and innate stimuli in youth but acquire intrinsic antigen-specific response defects in the elderly. In this article, we review how the identification of T_VM cells necessitates a re-evaluation of accepted paradigms for conventional memory T (T_MEM) cells, the potential for heterogeneity within the T_VM population, and the defining characteristics of T_VM cells. Further, we highlight recent literature documenting the development of T_VM cells as a distinct CD8⁺ T cell lineage as well their biological significance in the context of disease. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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15 pages, 715 KiB

Open AccessReview

Resident Memory T Cells and Their Role within the Liver

by Sonia Ghilas, Ana-Maria Valencia-Hernandez, Matthias H. Enders, William R. Heath and Daniel Fernandez-Ruiz

Int. J. Mol. Sci. 2020, 21(22), 8565; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228565 - 13 Nov 2020

Cited by 8 | Viewed by 4132

Abstract

Immunological memory is fundamental to maintain immunity against re-invading pathogens. It is the basis for prolonged protection induced by vaccines and can be mediated by humoral or cellular responses—the latter largely mediated by T cells. Memory T cells belong to different subsets with [...] Read more.

Immunological memory is fundamental to maintain immunity against re-invading pathogens. It is the basis for prolonged protection induced by vaccines and can be mediated by humoral or cellular responses—the latter largely mediated by T cells. Memory T cells belong to different subsets with specialized functions and distributions within the body. They can be broadly separated into circulating memory cells, which pace the entire body through the lymphatics and blood, and tissue-resident memory T (T_RM) cells, which are constrained to peripheral tissues. Retained in the tissues where they form, T_RM cells provide a frontline defense against reinfection. Here, we review this population of cells with specific attention to the liver, where T_RM cells have been found to protect against infections, in particular those by Plasmodium species that cause malaria. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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21 pages, 1773 KiB

Open AccessReview

Tfh Cells in Health and Immunity: Potential Targets for Systems Biology Approaches to Vaccination

by Hannah Law, Vanessa Venturi, Anthony Kelleher and C. Mee Ling Munier

Int. J. Mol. Sci. 2020, 21(22), 8524; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228524 - 12 Nov 2020

Cited by 21 | Viewed by 5242

Abstract

T follicular helper (Tfh) cells are a specialised subset of CD4+ T cells that play a significant role in the adaptive immune response, providing critical help to B cells within the germinal centres (GC) of secondary lymphoid organs. The B cell receptors of [...] Read more.

T follicular helper (Tfh) cells are a specialised subset of CD4+ T cells that play a significant role in the adaptive immune response, providing critical help to B cells within the germinal centres (GC) of secondary lymphoid organs. The B cell receptors of GC B cells undergo multiple rounds of somatic hypermutation and affinity maturation within the GC response, a process dependent on cognate interactions with Tfh cells. B cells that receive sufficient help from Tfh cells form antibody-producing long-lived plasma and memory B cells that provide the basis of decades of effective and efficient protection and are considered the gold standard in correlates of protection post-vaccination. However, the T cell response to vaccination has been understudied, and over the last 10 years, exponential improvements in the technological underpinnings of sampling techniques, experimental and analytical tools have allowed multidisciplinary characterisation of the role of T cells and the immune system as a whole. Of particular interest to the field of vaccinology are GCs and Tfh cells, representing a unique target for improving immunisation strategies. Here, we discuss recent insights into the unique journey of Tfh cells from thymus to lymph node during differentiation and their role in the production of high-quality antibody responses as well as their journey back to the periphery as a population of memory cells. Further, we explore their function in health and disease and the power of next-generation sequencing techniques to uncover their potential as modulators of vaccine-induced immunity. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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24 pages, 1023 KiB

Open AccessReview

Needle in a Haystack: The Naïve Repertoire as a Source of T Cell Receptors for Adoptive Therapy with Engineered T Cells

by Elvira D’Ippolito, Karolin I. Wagner and Dirk H Busch

Int. J. Mol. Sci. 2020, 21(21), 8324; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218324 - 06 Nov 2020

Cited by 4 | Viewed by 3689

Abstract

T cell engineering with antigen-specific T cell receptors (TCRs) has allowed the generation of increasingly specific, reliable, and versatile T cell products with near-physiological features. However, a broad applicability of TCR-based therapies in cancer is still limited by the restricted number of TCRs, [...] Read more.

T cell engineering with antigen-specific T cell receptors (TCRs) has allowed the generation of increasingly specific, reliable, and versatile T cell products with near-physiological features. However, a broad applicability of TCR-based therapies in cancer is still limited by the restricted number of TCRs, often also of suboptimal potency, available for clinical use. In addition, targeting of tumor neoantigens with TCR-engineered T cell therapy moves the field towards a highly personalized treatment, as tumor neoantigens derive from somatic mutations and are extremely patient-specific. Therefore, relevant TCRs have to be de novo identified for each patient and within a narrow time window. The naïve repertoire of healthy donors would represent a reliable source due to its huge diverse TCR repertoire, which theoretically entails T cells for any antigen specificity, including tumor neoantigens. As a challenge, antigen-specific naïve T cells are of extremely low frequency and mostly of low functionality, making the identification of highly functional TCRs finding a “needle in a haystack.” In this review, we present the technological advancements achieved in high-throughput mapping of patient-specific neoantigens and corresponding cognate TCRs and how these platforms can be used to interrogate the naïve repertoire for a fast and efficient identification of rare but therapeutically valuable TCRs for personalized adoptive T cell therapy. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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26 pages, 1224 KiB

Open AccessReview

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

by Xiaoliang Zhu and Jinfang Zhu

Int. J. Mol. Sci. 2020, 21(21), 8011; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218011 - 28 Oct 2020

Cited by 140 | Viewed by 23868

Abstract

The immune system plays a critical role in protecting hosts from the invasion of organisms. CD4 T cells, as a key component of the immune system, are central in orchestrating adaptive immune responses. After decades of investigation, five major CD4 T helper cell [...] Read more.

The immune system plays a critical role in protecting hosts from the invasion of organisms. CD4 T cells, as a key component of the immune system, are central in orchestrating adaptive immune responses. After decades of investigation, five major CD4 T helper cell (Th) subsets have been identified: Th1, Th2, Th17, Treg (T regulatory), and Tfh (follicular T helper) cells. Th1 cells, defined by the expression of lineage cytokine interferon (IFN)-γ and the master transcription factor T-bet, participate in type 1 immune responses to intracellular pathogens such as mycobacterial species and viruses; Th2 cells, defined by the expression of lineage cytokines interleukin (IL)-4/IL-5/IL-13 and the master transcription factor GAΤA3, participate in type 2 immune responses to larger extracellular pathogens such as helminths; Th17 cells, defined by the expression of lineage cytokines IL-17/IL-22 and the master transcription factor RORγt, participate in type 3 immune responses to extracellular pathogens including some bacteria and fungi; Tfh cells, by producing IL-21 and expressing Bcl6, help B cells produce corresponding antibodies; whereas Foxp3-expressing Treg cells, unlike Th1/Th2/Th17/Tfh exerting their effector functions, regulate immune responses to maintain immune cell homeostasis and prevent immunopathology. Interestingly, innate lymphoid cells (ILCs) have been found to mimic the functions of three major effector CD4 T helper subsets (Th1, Th2, and Th17) and thus can also be divided into three major subsets: ILC1s, ILC2s, and ILC3s. In this review, we will discuss the differentiation and functions of each CD4 T helper cell subset in the context of ILCs and human diseases associated with the dysregulation of these lymphocyte subsets particularly caused by monogenic mutations. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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22 pages, 1829 KiB

Open AccessReview

The Ups and Downs of Metabolism during the Lifespan of a T Cell

by Renu Balyan, Namrata Gautam and Nicholas R.J. Gascoigne

Int. J. Mol. Sci. 2020, 21(21), 7972; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217972 - 27 Oct 2020

Cited by 21 | Viewed by 3672

Abstract

Understanding the various mechanisms that govern the development, activation, differentiation, and functions of T cells is crucial as it could provide opportunities for therapeutic interventions to disrupt immune pathogenesis. Immunometabolism is one such area that has garnered significant interest in the recent past [...] Read more.

Understanding the various mechanisms that govern the development, activation, differentiation, and functions of T cells is crucial as it could provide opportunities for therapeutic interventions to disrupt immune pathogenesis. Immunometabolism is one such area that has garnered significant interest in the recent past as it has become apparent that cellular metabolism is highly dynamic and has a tremendous impact on the ability of T cells to grow, activate, and differentiate. In each phase of the lifespan of a T-cell, cellular metabolism has to be tailored to match the specific functional requirements of that phase. Resting T cells rely on energy-efficient oxidative metabolism but rapidly shift to a highly glycolytic metabolism upon activation in order to meet the bioenergetically demanding process of growth and proliferation. However, upon antigen clearance, T cells return to a more quiescent oxidative metabolism to support T cell memory generation. In addition, each helper T cell subset engages distinct metabolic pathways to support their functional needs. In this review, we provide an overview of the metabolic changes that occur during the lifespan of a T cell and discuss several important studies that provide insights into the regulation of the metabolic landscape of T cells and how they impact T cell development and function. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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20 pages, 6182 KiB

Open AccessReview

Relationship of 2D Affinity to T Cell Functional Outcomes

by Elizabeth M. Kolawole, Tracey J. Lamb and Brian D. Evavold

Int. J. Mol. Sci. 2020, 21(21), 7969; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217969 - 27 Oct 2020

Cited by 4 | Viewed by 3416

Abstract

T cells are critical for a functioning adaptive immune response and a strong correlation exists between T cell responses and T cell receptor (TCR): peptide-loaded MHC (pMHC) binding. Studies that utilize pMHC tetramer, multimers, and assays of three-dimensional (3D) affinity have provided advancements [...] Read more.

T cells are critical for a functioning adaptive immune response and a strong correlation exists between T cell responses and T cell receptor (TCR): peptide-loaded MHC (pMHC) binding. Studies that utilize pMHC tetramer, multimers, and assays of three-dimensional (3D) affinity have provided advancements in our understanding of T cell responses across different diseases. However, these technologies focus on higher affinity and avidity T cells while missing the lower affinity responders. Lower affinity TCRs in expanded polyclonal populations almost always constitute a significant proportion of the response with cells mediating different effector functions associated with variation in the proportion of high and low affinity T cells. Since lower affinity T cells expand and are functional, a fully inclusive view of T cell responses is required to accurately interpret the role of affinity for adaptive T cell immunity. For example, low affinity T cells are capable of inducing autoimmune disease and T cells with an intermediate affinity have been shown to exhibit an optimal anti-tumor response. Here, we focus on how affinity of the TCR may relate to T cell phenotype and provide examples where 2D affinity influences functional outcomes. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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18 pages, 1472 KiB

Open AccessReview

Lymph Node Stromal Cells: Mapmakers of T Cell Immunity

by Guillaume Harlé, Camille Kowalski, Laure Garnier and Stéphanie Hugues

Int. J. Mol. Sci. 2020, 21(20), 7785; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207785 - 21 Oct 2020

Cited by 14 | Viewed by 9129

Abstract

Stromal cells (SCs) are strategically positioned in both lymphoid and nonlymphoid organs to provide a scaffold and orchestrate immunity by modulating immune cell maturation, migration and activation. Recent characterizations of SCs have expanded our understanding of their heterogeneity and suggested a functional specialization [...] Read more.

Stromal cells (SCs) are strategically positioned in both lymphoid and nonlymphoid organs to provide a scaffold and orchestrate immunity by modulating immune cell maturation, migration and activation. Recent characterizations of SCs have expanded our understanding of their heterogeneity and suggested a functional specialization of distinct SC subsets, further modulated by the microenvironment. Lymph node SCs (LNSCs) have been shown to be particularly important in maintaining immune homeostasis and T cell tolerance. Under inflammation situations, such as viral infections or tumor development, SCs undergo profound changes in their numbers and phenotype and play important roles in contributing to either the activation or the control of T cell immunity. In this review, we highlight the role of SCs located in LNs in shaping peripheral T cell responses in different immune contexts, such as autoimmunity, viral and cancer immunity. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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17 pages, 994 KiB

Open AccessReview

Taming the Sentinels: Microbiome-Derived Metabolites and Polarization of T Cells

by Lukasz Wojciech, Kevin S. W. Tan and Nicholas R. J. Gascoigne

Int. J. Mol. Sci. 2020, 21(20), 7740; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207740 - 19 Oct 2020

Cited by 11 | Viewed by 3723

Abstract

A global increase in the prevalence of metabolic syndromes and digestive tract disorders, like food allergy or inflammatory bowel disease (IBD), has become a severe problem in the modern world. Recent decades have brought a growing body of evidence that links the gut [...] Read more.

A global increase in the prevalence of metabolic syndromes and digestive tract disorders, like food allergy or inflammatory bowel disease (IBD), has become a severe problem in the modern world. Recent decades have brought a growing body of evidence that links the gut microbiome’s complexity with host physiology. Hence, understanding the mechanistic aspects underlying the synergy between the host and its associated gut microbiome are among the most crucial questions. The functionally diversified adaptive immune system plays a central role in maintaining gut and systemic immune homeostasis. The character of the reciprocal interactions between immune components and host-dwelling microbes or microbial consortia determines the outcome of the organisms’ coexistence within the holobiont structure. It has become apparent that metabolic by-products of the microbiome constitute crucial multimodal transmitters within the host–microbiome interactome and, as such, contribute to immune homeostasis by fine-tuning of the adaptive arm of immune system. In this review, we will present recent insights and discoveries regarding the broad landscape of microbiome-derived metabolites, highlighting the role of these small compounds in the context of the balance between pro- and anti-inflammatory mechanisms orchestrated by the host T cell compartment. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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14 pages, 2103 KiB

Open AccessReview

Unconventional Peptide Presentation by Classical MHC Class I and Implications for T and NK Cell Activation

by Dirk M. Zajonc

Int. J. Mol. Sci. 2020, 21(20), 7561; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207561 - 13 Oct 2020

Cited by 7 | Viewed by 3285

Abstract

T cell-mediated immune recognition of peptides is initiated upon binding of the antigen receptor on T cells (TCR) to the peptide-MHC complex. TCRs are typically restricted by a particular MHC allele, while polymorphism within the MHC molecule can affect the spectrum of peptides [...] Read more.

T cell-mediated immune recognition of peptides is initiated upon binding of the antigen receptor on T cells (TCR) to the peptide-MHC complex. TCRs are typically restricted by a particular MHC allele, while polymorphism within the MHC molecule can affect the spectrum of peptides that are bound and presented to the TCR. Classical MHC Class I molecules have a confined binding groove that restricts the length of the presented peptides to typically 8–11 amino acids. Both N- and C-termini of the peptide are bound within binding pockets, allowing the TCR to dock in a diagonal orientation above the MHC-peptide complex. Longer peptides have been observed to bind either in a bulged or zig-zag orientation within the binding groove. More recently, unconventional peptide presentation has been reported for different MHC I molecules. Here, either N- or C-terminal amino acid additions to conventionally presented peptides induced a structural change either within the MHC I molecule that opened the confined binding groove or within the peptide itself, allowing the peptide ends to protrude into the solvent. Since both TCRs on T cells and killer immunoglobulin receptors on Natural Killer (NK) cells contact the MHC I molecule above or at the periphery of the peptide binding groove, unconventionally presented peptides could modulate both T cell and NK cell responses. We will highlight recent advances in our understanding of the functional consequences of unconventional peptide presentation in cellular immunity. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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26 pages, 2997 KiB

Open AccessReview

T Cell Activation Machinery: Form and Function in Natural and Engineered Immune Receptors

by Nicholas J. Chandler, Melissa J. Call and Matthew E. Call

Int. J. Mol. Sci. 2020, 21(19), 7424; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197424 - 08 Oct 2020

Cited by 9 | Viewed by 7743

Abstract

The impressive success of chimeric antigen receptor (CAR)-T cell therapies in treating advanced B-cell malignancies has spurred a frenzy of activity aimed at developing CAR-T therapies for other cancers, particularly solid tumors, and optimizing engineered T cells for maximum clinical benefit in many [...] Read more.

The impressive success of chimeric antigen receptor (CAR)-T cell therapies in treating advanced B-cell malignancies has spurred a frenzy of activity aimed at developing CAR-T therapies for other cancers, particularly solid tumors, and optimizing engineered T cells for maximum clinical benefit in many different disease contexts. A rapidly growing body of design work is examining every modular component of traditional single-chain CARs as well as expanding out into many new and innovative engineered immunoreceptor designs that depart from this template. New approaches to immune cell and receptor engineering are being reported with rapidly increasing frequency, and many recent high-quality reviews (including one in this special issue) provide comprehensive coverage of the history and current state of the art in CAR-T and related cellular immunotherapies. In this review, we step back to examine our current understanding of the structure-function relationships in natural and engineered lymphocyte-activating receptors, with an eye towards evaluating how well the current-generation CAR designs recapitulate the most desirable features of their natural counterparts. We identify key areas that we believe are under-studied and therefore represent opportunities to further improve our grasp of form and function in natural and engineered receptors and to rationally design better therapeutics. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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28 pages, 1510 KiB

Open AccessReview

Cellular and Molecular Mechanisms of CD8⁺ T Cell Differentiation, Dysfunction and Exhaustion

by Daniel J. Verdon, Matthias Mulazzani and Misty R. Jenkins

Int. J. Mol. Sci. 2020, 21(19), 7357; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197357 - 05 Oct 2020

Cited by 41 | Viewed by 12181

Abstract

T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically “exhausted” in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and [...] Read more.

T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically “exhausted” in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and gain constitutive expression of a broad coinhibitory receptor suite. This review outlines recent advances in our understanding of exhausted T cell biology and examines cellular and molecular mechanisms by which a state of dysfunction or exhaustion is established, and mechanisms by which exhausted T cells may still contribute to pathogen or tumour control. Further, this review describes our understanding of exhausted T cell heterogeneity and outlines the mechanisms by which checkpoint blockade differentially engages exhausted T cell subsets to overcome exhaustion and recover T cell function. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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18 pages, 1804 KiB

Open AccessReview

Treg Enhancing Therapies to Treat Autoimmune Diseases

by Peter J. Eggenhuizen, Boaz H. Ng and Joshua D. Ooi

Int. J. Mol. Sci. 2020, 21(19), 7015; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197015 - 23 Sep 2020

Cited by 120 | Viewed by 17331

Abstract

Regulatory T cells (Tregs) are a small yet critical subset of CD4+ T cells, which have the role of maintaining immune homeostasis by, for example, regulating self-tolerance, tumor immunity, anti-microbial resistance, allergy and transplantation rejection. The suppressive mechanisms by which Tregs function are [...] Read more.

Regulatory T cells (Tregs) are a small yet critical subset of CD4+ T cells, which have the role of maintaining immune homeostasis by, for example, regulating self-tolerance, tumor immunity, anti-microbial resistance, allergy and transplantation rejection. The suppressive mechanisms by which Tregs function are varied and pleiotropic. The ability of Tregs to maintain self-tolerance means they are critical for the control and prevention of autoimmune diseases. Irregularities in Treg function and number can result in loss of tolerance and autoimmune disease. Restoring immune homeostasis and tolerance through the promotion, activation or delivery of Tregs has emerged as a focus for therapies aimed at curing or controlling autoimmune diseases. Such therapies have focused on the Treg cell subset by using drugs to suppress T effector cells and promote Tregs. Other approaches have trialed inducing tolerance by administering the autoantigen via direct administration, by transient expression using a DNA vector, or by antigen-specific nanoparticles. More recently, cell-based therapies have been developed as an approach to directly or indirectly enhance Treg cell specificity, function and number. This can be achieved indirectly by transfer of tolerogenic dendritic cells, which have the potential to expand antigen-specific Treg cells. Treg cells can be directly administered to treat autoimmune disease by way of polyclonal Tregs or Tregs transduced with a receptor with high affinity for the target autoantigen, such as a high affinity T cell receptor (TCR) or a chimeric antigen receptor (CAR). This review will discuss the strategies being developed to redirect autoimmune responses to a state of immune tolerance, with the aim of the prevention or amelioration of autoimmune disease. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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16 pages, 1529 KiB

Open AccessReview

IL-21 in Homeostasis of Resident Memory and Exhausted CD8 T Cells during Persistent Infection

by Heather M. Ren and Aron E. Lukacher

Int. J. Mol. Sci. 2020, 21(18), 6966; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186966 - 22 Sep 2020

Cited by 8 | Viewed by 5492

Abstract

CD4 T cells guide the development of CD8 T cells into memory by elaborating mitogenic and differentiation factors and by licensing professional antigen-presenting cells. CD4 T cells also act to stave off CD8 T cell dysfunction during repetitive antigen stimulation in persistent infection [...] Read more.

CD4 T cells guide the development of CD8 T cells into memory by elaborating mitogenic and differentiation factors and by licensing professional antigen-presenting cells. CD4 T cells also act to stave off CD8 T cell dysfunction during repetitive antigen stimulation in persistent infection and cancer by mitigating generation of exhausted T cells (T_EX). CD4 T cell help is also required for establishing and maintaining tissue-resident memory T cells (T_RM), the nonrecirculating memory T cell subset parked in nonlymphoid tissues to provide frontline defense against reinvading pathogens. Interleukin (IL)-21 is the signature cytokine secreted by follicular helper CD4 T cells (T_FH) to drive B cell expansion and differentiation in germinal centers to mount high-affinity, isotype class-switched antibodies. In several infection models, IL-21 has been identified as the CD4 T help needed for formation and survival of T_RM and T_EX. In this review, we will explore the different memory subsets of CD8 T cells in persistent infections, the metabolic profiles associated with each, and evidence documenting the importance of CD4 T cell-derived IL-21 in regulating CD8 T_RM and T_EX development, homeostasis, and function. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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16 pages, 1013 KiB

Open AccessReview

The Transcription Factor TCF1 in T Cell Differentiation and Aging

by Chulwoo Kim, Jun Jin, Cornelia M. Weyand and Jörg J. Goronzy

Int. J. Mol. Sci. 2020, 21(18), 6497; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186497 - 05 Sep 2020

Cited by 42 | Viewed by 12399

Abstract

The transcription factor T cell factor 1 (TCF1), a pioneer transcription factor as well as a downstream effector of WNT/β-catenin signaling, is indispensable for T cell development in the thymus. Recent studies have highlighted the additional critical role of TCF1 in peripheral T [...] Read more.

The transcription factor T cell factor 1 (TCF1), a pioneer transcription factor as well as a downstream effector of WNT/β-catenin signaling, is indispensable for T cell development in the thymus. Recent studies have highlighted the additional critical role of TCF1 in peripheral T cell responses to acute and chronic infections as well as cancer. Here, we review the regulatory functions of TCF1 in the differentiation of T follicular helper cells, memory T cells and recently described stem-like exhausted T cells, where TCF1 promotes less differentiated stem-like cell states by controlling common gene-regulatory networks. These studies also provide insights into the mechanisms of defective T cell responses in older individuals. We discuss alterations in TCF1 expression and related regulatory networks with age and their consequences for T cell responses to infections and vaccination. The increasing understanding of the pathways regulating TCF1 expression and function in aged T cells holds the promise of enabling the design of therapeutic interventions aiming at improving T cell responses in older individuals. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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32 pages, 1206 KiB

Open AccessReview

T Cell Immunity to Bacterial Pathogens: Mechanisms of Immune Control and Bacterial Evasion

by Freya R. Shepherd and James E. McLaren

Int. J. Mol. Sci. 2020, 21(17), 6144; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176144 - 26 Aug 2020

Cited by 45 | Viewed by 5120

Abstract

The human body frequently encounters harmful bacterial pathogens and employs immune defense mechanisms designed to counteract such pathogenic assault. In the adaptive immune system, major histocompatibility complex (MHC)-restricted αβ T cells, along with unconventional αβ or γδ T cells, respond to bacterial antigens [...] Read more.

The human body frequently encounters harmful bacterial pathogens and employs immune defense mechanisms designed to counteract such pathogenic assault. In the adaptive immune system, major histocompatibility complex (MHC)-restricted αβ T cells, along with unconventional αβ or γδ T cells, respond to bacterial antigens to orchestrate persisting protective immune responses and generate immunological memory. Research in the past ten years accelerated our knowledge of how T cells recognize bacterial antigens and how many bacterial species have evolved mechanisms to evade host antimicrobial immune responses. Such escape mechanisms act to corrupt the crosstalk between innate and adaptive immunity, potentially tipping the balance of host immune responses toward pathological rather than protective. This review examines the latest developments in our knowledge of how T cell immunity responds to bacterial pathogens and evaluates some of the mechanisms that pathogenic bacteria use to evade such T cell immunosurveillance, to promote virulence and survival in the host. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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13 pages, 689 KiB

Open AccessReview

Dietary Regulation of Memory T Cells

by Nicholas Collins

Int. J. Mol. Sci. 2020, 21(12), 4363; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124363 - 19 Jun 2020

Cited by 12 | Viewed by 4628

Abstract

Memory T cells are a fundamental component of immunological memory, providing rapid and potent host protection against secondary challenges. As such, memory T cells are key targets in the design of vaccination strategies and cancer immunotherapies, making it critical to understand the factors [...] Read more.

Memory T cells are a fundamental component of immunological memory, providing rapid and potent host protection against secondary challenges. As such, memory T cells are key targets in the design of vaccination strategies and cancer immunotherapies, making it critical to understand the factors and mechanisms that regulate their biology. Diet is an environmental feature that impacts virtually all aspects of host physiology. However, the influence of specific dietary regiments and nutritional components on the immune system is only just starting to be uncovered. This article will review literature regarding the impact of diet and nutrition on memory T cell development, maintenance and function. It was recently shown that caloric restriction without undernutrition enhances memory T cell function, while diets high in fiber are also beneficial. However, memory T cell responses are dysfunctional in extreme nutritional states, such as undernutrition and diet-induced obesity. Therefore, diet and host nutritional status are major regulators of memory T cell biology and host fitness. To define the dietary balance required to promote optimal memory T cell responses could allow for the implementation of rational diet-based therapies that prevent or treat disease. Furthermore, that certain dietary regiments can enhance memory T cell function indicates the possibility of harnessing the underlying mechanisms in the design of novel vaccination strategies and cancer immunotherapies. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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22 pages, 764 KiB

Open AccessReview

Novel Therapies Boosting T Cell Immunity in Epstein Barr Virus-Associated Nasopharyngeal Carcinoma

by Sarah Renaud, Anthony Lefebvre, Serge Mordon, Olivier Moralès and Nadira Delhem

Int. J. Mol. Sci. 2020, 21(12), 4292; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124292 - 16 Jun 2020

Cited by 14 | Viewed by 3808

Abstract

Nasopharyngeal carcinoma (NPC) is a malignant tumour of the head and neck affecting localised regions of the world, with the highest rates described in Southeast Asia, Northern Africa, and Greenland. Its high morbidity rate is linked to both late-stage diagnosis and unresponsiveness to [...] Read more.

Nasopharyngeal carcinoma (NPC) is a malignant tumour of the head and neck affecting localised regions of the world, with the highest rates described in Southeast Asia, Northern Africa, and Greenland. Its high morbidity rate is linked to both late-stage diagnosis and unresponsiveness to conventional anti-cancer treatments. Multiple aetiological factors have been described including environmental factors, genetics, and viral factors (Epstein Barr Virus, EBV), making NPC treatment that much more complex. The most common forms of NPCs are those that originate from the epithelial tissue lining the nasopharynx and are often linked to EBV infection. Indeed, they represent 75–95% of NPCs in the low-risk populations and almost 100% of NPCs in high-risk populations. Although conventional surgery has been improved with nasopharyngectomy’s being carried out using more sophisticated surgical equipment for better tumour resection, recent findings in the tumour microenvironment have led to novel treatment options including immunotherapies and photodynamic therapy, able to target the tumour and improve the immune system. This review provides an update on the disease’s aetiology and the future of NPC treatments with a focus on therapies activating T cell immunity. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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30 pages, 1347 KiB

Open AccessReview

CARs: Beyond T Cells and T Cell-Derived Signaling Domains

by Nico M. Sievers, Jan Dörrie and Niels Schaft

Int. J. Mol. Sci. 2020, 21(10), 3525; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103525 - 15 May 2020

Cited by 20 | Viewed by 5372

Abstract

When optimizing chimeric antigen receptor (CAR) therapy in terms of efficacy, safety, and broadening its application to new malignancies, there are two main clusters of topics to be addressed: the CAR design and the choice of transfected cells. The former focuses on the [...] Read more.

When optimizing chimeric antigen receptor (CAR) therapy in terms of efficacy, safety, and broadening its application to new malignancies, there are two main clusters of topics to be addressed: the CAR design and the choice of transfected cells. The former focuses on the CAR construct itself. The utilized transmembrane and intracellular domains determine the signaling pathways induced by antigen binding and thereby the cell-specific effector functions triggered. The main part of this review summarizes our understanding of common signaling domains employed in CARs, their interactions among another, and their effects on different cell types. It will, moreover, highlight several less common extracellular and intracellular domains that might permit unique new opportunities. Different antibody-based extracellular antigen-binding domains have been pursued and optimized to strike a balance between specificity, affinity, and toxicity, but these have been reviewed elsewhere. The second cluster of topics is about the cellular vessels expressing the CAR. It is essential to understand the specific attributes of each cell type influencing anti-tumor efficacy, persistence, and safety, and how CAR cells crosstalk with each other and bystander cells. The first part of this review focuses on the progress achieved in adopting different leukocytes for CAR therapy. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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16 pages, 3261 KiB

Open AccessCase Report

Combination of High Dose Hypofractionated Radiotherapy with Anti-PD1 Single Dose Immunotherapy Leads to a Th1 Immune Activation Resulting in a Complete Clinical Response in a Melanoma Patient

by Clara Milhem, Olivier Moralès, Céline Ingelaere, David Pasquier, Serge Mordon, Laurent Mortier, Xavier Mirabel and Nadira Delhem

Int. J. Mol. Sci. 2020, 21(18), 6772; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186772 - 15 Sep 2020

Cited by 3 | Viewed by 2272

Abstract

The development of immunotherapy has recently modified the anti-tumor therapeutic arsenal; particularly, immune checkpoint inhibitors have led to a significant increase in overall survival. The current challenge is now to select good responder patients by identifying early biomarkers to propose therapeutic combinations that [...] Read more.

The development of immunotherapy has recently modified the anti-tumor therapeutic arsenal; particularly, immune checkpoint inhibitors have led to a significant increase in overall survival. The current challenge is now to select good responder patients by identifying early biomarkers to propose therapeutic combinations that potentiate the efficacy of the therapy. Here we report the case of a 60-year-old man with superficial melanoma treated with high-dose hypo fractionated radiotherapy (H-SRT) combined with a single dose of anti-PD1 immunotherapy (Nivolumab) for a metastatic lymph node recurrence due to cancer progression. In this study, we present the results obtained regarding the activation of the Th1 immune response after H-SRT treatment followed by anti PD-1 therapeutic protocol. These results were correlated with clinical data to identify potential immunological biomarkers of treatment efficacy. This exceptional case report shows that a combination of H-SRT with a single dose of anti-PD1 immunotherapy may allow a better activation of the immune response in favor of a complete clinical response. Full article

(This article belongs to the Special Issue Recent Advances in T Cell Immunity)

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