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The Many Facets of the Regulation of TCR Signaling
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The Many Facets of the Regulation of TCR Signaling

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 12432

Special Issue Editors

Prof. Dr. Luca Simeoni

E-Mail Website
Guest Editor
Health Campus Immunology, Infectiology, and Inflammation, Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Str. 44, D-39120 Magdeburg, Germany
Interests: lymphocyte signaling; T-cell receptor signaling; Zap70; Lck; tyrosine kinases; T-cell activation; thymic development; natural products; immunomodulation
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Ursula Bommhardt

E-Mail Website
Guest Editor
Magdeburg Health Campus Immunology, Infectiology, and Inflammation, Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Str. 44, D-39120 Magdeburg, Germany
Interests: T cell
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

T cells are well-known for their importance in the orchestration of the adaptive immune response. Alterations in the function of T cells are at the basis of many inflammatory disorders including autoimmune diseases, allergy, transplant rejection, reperfusion injury, and cancer as well as in immunodeficiency. T-cell functions critically depend on signaling cascades triggered upon the engagement of the T-cell receptor (TCR). The experimental evidence accumulated over the past decades has demonstrated that the TCR regulates development, activation, differentiation, and homeostasis of T cells. How signaling via a single receptor can dictate different cellular outcomes has intrigued many researchers. It has become clearer that the intensity and the duration of TCR signaling and its integration with signaling cascades downstream of other cell surface receptors operate in concert to dictate the specific cell fate and response.

In this Special Issue, we invite investigators to submit original research or review articles on the many facets in the regulation of TCR signaling.

Topics include but are not limited to the following:

  • Dynamic changes of TCR conformation and initiation of TCR signaling
  • Orchestration of proximal signaling events
  • Propagation of TCR signaling and initiation of transcription
  • Signaling molecules: adaptors, kinases, phosphatases, etc.
  • Integration of TCR signaling: co-stimulatory molecules
  • Inhibition of TCR signaling
  • TCR signal strength and TCR signaling dynamics
  • Modeling of TCR signaling
  • Redox-mediated regulation of TCR signaling
  • Engineered TCRs: signaling via CARs

Prof. Luca Simeoni
Prof. Ursula Bommhardt
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (5 papers)

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Research

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9 pages, 1966 KiB  
Article
Erythroid Differentiation Regulator 1 Strengthens TCR Signaling by Enhancing PLCγ1 Signal Transduction Pathway
by Myun Soo Kim, Dongmin Park, Sora Lee, Sunyoung Park, Kyung Eun Kim, Tae Sung Kim, Hyun Jeong Park and Daeho Cho
Int. J. Mol. Sci. 2022, 23(2), 844; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020844 - 13 Jan 2022
Cited by 2 | Viewed by 1462
Abstract
Erythroid differentiation regulator 1 (Erdr1) has previously been reported to control thymocyte selection via TCR signal regulation, but the effect of Erdr1 as a TCR signaling modulator was not studied in peripheral T cells. In this report, it was determined whether Erdr1 affected [...] Read more.
Erythroid differentiation regulator 1 (Erdr1) has previously been reported to control thymocyte selection via TCR signal regulation, but the effect of Erdr1 as a TCR signaling modulator was not studied in peripheral T cells. In this report, it was determined whether Erdr1 affected TCR signaling strength in CD4 T cells. Results revealed that Erdr1 significantly enhanced the anti-TCR antibody-mediated activation and proliferation of T cells while failing to activate T cells in the absence of TCR stimulation. In addition, Erdr1 amplified Ca2+ influx and the phosphorylation of PLCγ1 in CD4 T cells with the TCR stimuli. Furthermore, NFAT1 translocation into nuclei in CD4 T cells was also significantly promoted by Erdr1 in the presence of TCR stimulation. Taken together, our results indicate that Erdr1 positively modulates TCR signaling strength via enhancing the PLCγ1/Ca2+/NFAT1 signal transduction pathway. Full article
(This article belongs to the Special Issue The Many Facets of the Regulation of TCR Signaling)
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17 pages, 2944 KiB  
Article
Cross-TCR Antagonism Revealed by Optogenetically Tuning the Half-Life of the TCR Ligand Binding
by Omid Sascha Yousefi, Matias Ruggieri, Vincent Idstein, Kai Uwe von Prillwitz, Laurenz A. Herr, Julia Chalupsky, Maja Köhn, Wilfried Weber, Jens Timmer and Wolfgang W. A. Schamel
Int. J. Mol. Sci. 2021, 22(9), 4920; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094920 - 06 May 2021
Cited by 5 | Viewed by 2595
Abstract
Activation of T cells by agonistic peptide-MHC can be inhibited by antagonistic ones. However, the exact mechanism remains elusive. We used Jurkat cells expressing two different TCRs and tested whether stimulation of the endogenous TCR by agonistic anti-Vβ8 antibodies can be modulated by [...] Read more.
Activation of T cells by agonistic peptide-MHC can be inhibited by antagonistic ones. However, the exact mechanism remains elusive. We used Jurkat cells expressing two different TCRs and tested whether stimulation of the endogenous TCR by agonistic anti-Vβ8 antibodies can be modulated by ligand-binding to the second, optogenetic TCR. The latter TCR uses phytochrome B tetramers (PhyBt) as ligand, the binding half-life of which can be altered by light. We show that this half-life determined whether the PhyBt acted as a second agonist (long half-life), an antagonist (short half-life) or did not have any influence (very short half-life) on calcium influx. A mathematical model of this cross-antagonism shows that a mechanism based on an inhibitory signal generated by early recruitment of a phosphatase and an activating signal by later recruitment of a kinase explains the data. Full article
(This article belongs to the Special Issue The Many Facets of the Regulation of TCR Signaling)
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12 pages, 1799 KiB  
Article
The Activity and Stability of p56Lck and TCR Signaling Do Not Depend on the Co-Chaperone Cdc37
by Sarah Kowallik, Andreas Kritikos, Matthias Kästle, Christoph Thurm, Burkhart Schraven and Luca Simeoni
Int. J. Mol. Sci. 2021, 22(1), 126; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010126 - 24 Dec 2020
Cited by 1 | Viewed by 2217
Abstract
Lymphocyte-specific protein tyrosine kinase (Lck) is a pivotal tyrosine kinase involved in T cell receptor (TCR) signaling. Because of its importance, the activity of Lck is regulated at different levels including phosphorylation of tyrosine residues, protein–protein interactions, and localization. It has been proposed [...] Read more.
Lymphocyte-specific protein tyrosine kinase (Lck) is a pivotal tyrosine kinase involved in T cell receptor (TCR) signaling. Because of its importance, the activity of Lck is regulated at different levels including phosphorylation of tyrosine residues, protein–protein interactions, and localization. It has been proposed that the co-chaperone Cdc37, which assists the chaperone heat shock protein 90 (Hsp90) in the folding of client proteins, is also involved in the regulation of the activity/stability of Lck. Nevertheless, the available experimental data do not clearly support this conclusion. Thus, we assessed whether or not Cdc37 regulates Lck. We performed experiments in which the expression of Cdc37 was either augmented or suppressed in Jurkat T cells. The results of our experiments indicated that neither the overexpression nor the suppression of Cdc37 affected Lck stability and activity. Moreover, TCR signaling proceeded normally in T cells in which Cdc37 expression was either augmented or suppressed. Finally, we demonstrated that also under stress conditions Cdc37 was dispensable for the regulation of Lck activity/stability. In conclusion, our data do not support the idea that Lck is a Cdc37 client. Full article
(This article belongs to the Special Issue The Many Facets of the Regulation of TCR Signaling)
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13 pages, 2304 KiB  
Article
Agent-Based Modeling of T Cell Receptor Cooperativity
by Anastasios Siokis, Philippe A. Robert and Michael Meyer-Hermann
Int. J. Mol. Sci. 2020, 21(18), 6473; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186473 - 04 Sep 2020
Cited by 1 | Viewed by 2595
Abstract
Immunological synapse (IS) formation is a key event during antigen recognition by T cells. Recent experimental evidence suggests that the affinity between T cell receptors (TCRs) and antigen is actively modulated during the early steps of TCR signaling. In this work, we used [...] Read more.
Immunological synapse (IS) formation is a key event during antigen recognition by T cells. Recent experimental evidence suggests that the affinity between T cell receptors (TCRs) and antigen is actively modulated during the early steps of TCR signaling. In this work, we used an agent-based model to study possible mechanisms for affinity modulation during IS formation. We show that, without any specific active mechanism, the observed affinity between receptors and ligands evolves over time and depends on the density of ligands of the antigen peptide presented by major histocompatibility complexes (pMHC) and TCR molecules. A comparison between the presence or absence of TCR–pMHC centrally directed flow due to F-actin coupling suggests that centripetal transport is a potential mechanism for affinity modulation. The model further suggests that the time point of affinity measurement during immune synapse formation is critical. Finally, a mathematical model of F-actin foci formation incorporated in the agent-based model shows that TCR affinity can potentially be actively modulated by positive/negative feedback of the F-actin foci on the TCR-pMHC association rate kon. Full article
(This article belongs to the Special Issue The Many Facets of the Regulation of TCR Signaling)
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Review

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15 pages, 1655 KiB  
Review
MicroRNA miR-181—A Rheostat for TCR Signaling in Thymic Selection and Peripheral T-Cell Function
by Zoe Grewers and Andreas Krueger
Int. J. Mol. Sci. 2020, 21(17), 6200; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176200 - 27 Aug 2020
Cited by 15 | Viewed by 3015
Abstract
The selection of T cells during intra-thymic d evelopment is crucial to obtain a functional and simultaneously not self-reactive peripheral T cell repertoire. However, selection is a complex process dependent on T cell receptor (TCR) thresholds that remain incompletely understood. In peripheral T [...] Read more.
The selection of T cells during intra-thymic d evelopment is crucial to obtain a functional and simultaneously not self-reactive peripheral T cell repertoire. However, selection is a complex process dependent on T cell receptor (TCR) thresholds that remain incompletely understood. In peripheral T cells, activation, clonal expansion, and contraction of the active T cell pool, as well as other processes depend on TCR signal strength. Members of the microRNA (miRNA) miR-181 family have been shown to be dynamically regulated during T cell development as well as dependent on the activation stage of T cells. Indeed, it has been shown that expression of miR-181a leads to the downregulation of multiple phosphatases, implicating miR-181a as ‘‘rheostat’’ of TCR signaling. Consistently, genetic models have revealed an essential role of miR-181a/b-1 for the generation of unconventional T cells as well as a function in tuning TCR sensitivity in peripheral T cells during aging. Here, we review these broad roles of miR-181 family members in T cell function via modulating TCR signal strength. Full article
(This article belongs to the Special Issue The Many Facets of the Regulation of TCR Signaling)
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