scholarly journals N6-adenosine methylation of mRNAs requires Wtap expression and controls T cell receptor signaling and survival

2021 ◽  
Author(s):  
Vigo Heissmeyer ◽  
Taku Ito-Kureha ◽  
Cristina Leoni ◽  
Kayla Borland ◽  
Marian Bataclan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transcriptional Repression ◽  
Cell Function ◽  
Complex Function ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
T Cell Receptor Signaling ◽  
Tcr Signal Transduction ◽  
Store Operated Calcium Entry

Abstract T cell antigen receptor (TCR) signaling controls the development, activation and survival of T cells by involving several layers and numerous mechanisms of gene regulation. N6-methyladenosine (m6A) is the most prevalent mRNA modification affecting splicing, translation and stability of transcripts. Here, we describe the Wtap protein as essential for m6A methyltransferase complex function and reveal its crucial role in TCR signaling. Wtap and m6A methyltransferase functions were required for the differentiation of thymocytes, control of activation-induced death of peripheral T cells and prevention of colitis by enabling gut RORγt+ regulatory T cell function. Transcriptome and epitranscriptomic analyses reveal that m6A modification destabilizes Orai1 and Ripk1 mRNAs. Lack of post-transcriptional repression of the encoded proteins correlated with increased store-operated calcium entry (SOCE) activity and diminished survival of T cells. These findings uncover how m6A modification impacts on TCR signal transduction and determines activation and survival of T cells.

scholarly journals Exhausted CD8+ T cells exhibit low and strongly inhibited TCR signaling during chronic LCMV infection

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ioana Sandu ◽  
Dario Cerletti ◽  
Manfred Claassen ◽  
Annette Oxenius
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Viral Infections ◽  
Cell Receptor ◽  
Target Cells ◽  
Tcr Signaling ◽  
And Function

Abstract Chronic viral infections are often associated with impaired CD8+ T cell function, referred to as exhaustion. Although the molecular and cellular circuits involved in CD8+ T cell exhaustion are well defined, with sustained presence of antigen being one important parameter, how much T cell receptor (TCR) signaling is actually ongoing in vivo during established chronic infection is unclear. Here, we characterize the in vivo TCR signaling of virus-specific exhausted CD8+ T cells in a mouse model, leveraging TCR signaling reporter mice in combination with transcriptomics. In vivo signaling in exhausted cells is low, in contrast to their in vitro signaling potential, and despite antigen being abundantly present. Both checkpoint blockade and adoptive transfer of naïve target cells increase TCR signaling, demonstrating that engagement of co-inhibitory receptors curtails CD8+ T cell signaling and function in vivo.

scholarly journals MicroRNA miR-181—A Rheostat for TCR Signaling in Thymic Selection and Peripheral T-Cell Function

2020 ◽  
Vol 21 (17) ◽  
pp. 6200
Author(s):  
Zoe Grewers ◽  
Andreas Krueger
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Signal Strength ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Cell Repertoire ◽  
T Cell Function ◽  
Complex Process ◽  
Peripheral T Cells

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.

scholarly journals Induction of T Cell Senescence by Cytokine Induced Bystander Activation

2021 ◽  
Vol 2 ◽  
Author(s):  
Attiya A. Abbas ◽  
Arne N. Akbar
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Critical Role ◽  
The Elderly ◽  
Cell Receptor ◽  
Antigen Specificity ◽  
Tcr Signaling ◽  
Bystander Activation

As people around the world continue to live longer, maintaining a good quality of life is of increasing importance. The COVID-19 pandemic revealed that the elderly are disproportionally vulnerable to infectious diseases and Immunosenescence plays a critical role in that. An ageing immune system influences the conventional activity of T cells which are at the forefront of eliminating harmful foreign antigens. With ageing, unconventional end-stage T cells, that exhibit a senescent phenotype, amass. These senescent T cells deviate from T cell receptor (TCR) signaling toward natural killer (NK) activity. The transition toward innate immune cell function from these adaptor T cells impacts antigen specificity, contributing to increased susceptibility of infection in the elderly. The mechanism by which senescent T cells arise remains largely unclear however in this review we investigate the part that bystander activation plays in driving the change in function of T cells with age. Cytokine-induced bystander activation may offer a plausible explanation for the induction of NK-like activity and senescence in T cells. Further understanding of these specific NK-like senescent T cells allows us to identify the benefits and detriments of these cells in health and disease which can be utilized or regulated, respectively. This review discusses the dynamic of senescent T cells in adopting NK-like T cells and the implications that has in an infectious disease context, predominately in the elderly.

scholarly journals Presenilins regulate αβ T cell development by modulating TCR signaling

2007 ◽  
Vol 204 (9) ◽  
pp. 2115-2129 ◽  
Author(s):  
Karen Laky ◽  
B.J. Fowlkes
Keyword(s):  
T Cells ◽  
T Cell ◽  
Notch Signaling ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Notch Signaling Pathway ◽  
Tcr Signaling ◽  
Tcr Signal Transduction ◽  
Genes Encoding

TCRαβ signaling is crucial for the maturation of CD4 and CD8 T cells, but the role of the Notch signaling pathway in this process is poorly understood. Genes encoding Presenilin (PS) 1/2 were deleted to prevent activation of the multiple Notch receptors expressed by developing thymocytes. PS1/2 knockout thymocyte precursors inefficiently generate CD4 T cells, a phenotype that is most pronounced when thymocytes bear a single major histocompatibility complex (MHC) class II–restricted T cell receptor (TCR). Diminished T cell production correlated with evidence of impaired TCR signaling, and could be rescued by manipulations that enhance MHC recognition. Although Notch appears to directly regulate binary fate decisions in many systems, these findings suggest a model in which PS-dependent Notch signaling influences positive selection and the development of αβ T cells by modifying TCR signal transduction.

scholarly journals Naturally Occurring Genetic Alterations in Proximal TCR Signaling and Implications for Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Andrew Kent ◽  
Natalie V. Longino ◽  
Allison Christians ◽  
Eduardo Davila
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Cell Activity ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Receptor ◽  
Genetic Alterations ◽  
Immune Checkpoint Blockade ◽  
Genetically Engineered ◽  
Tcr Signaling

T cell-based immunotherapies including genetically engineered T cells, adoptive transfer of tumor-infiltrating lymphocytes, and immune checkpoint blockade highlight the impressive anti-tumor effects of T cells. These successes have provided new hope to many cancer patients with otherwise poor prognoses. However, only a fraction of patients demonstrates durable responses to these forms of therapies and many develop significant immune-mediated toxicity. These heterogeneous clinical responses suggest that underlying nuances in T cell genetics, phenotypes, and activation states likely modulate the therapeutic impact of these approaches. To better characterize known genetic variations that may impact T cell function, we 1) review the function of early T cell receptor-specific signaling mediators, 2) offer a synopsis of known mutations and genetic alterations within the associated molecules, 3) discuss the link between these mutations and human disease and 4) review therapeutic strategies under development or in clinical testing that target each of these molecules for enhancing anti-tumor T cell activity. Finally, we discuss novel engineering approaches that could be designed based on our understanding of the function of these molecules in health and disease.

scholarly journals Targeting CAR to the Peptide-MHC Complex Reveals Distinct Signaling Compared to That of TCR in a Jurkat T Cell Model

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 867
Author(s):  
Ling Wu ◽  
Joanna Brzostek ◽  
Shvetha Sankaran ◽  
Qianru Wei ◽  
Jiawei Yap ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Model ◽  
Cell Receptor ◽  
Target Cells ◽  
Tcr Signaling ◽  
Barr Virus ◽  
Car T ◽  
Epstein Barr ◽  
Lower Magnitude

Chimeric antigen receptor T cells (CAR-T) utilize T cell receptor (TCR) signaling cascades and the recognition functions of antibodies. This allows T cells, normally restricted by the major histocompatibility complex (MHC), to be redirected to target cells by their surface antigens, such as tumor associated antigens (TAAs). CAR-T technology has achieved significant successes in treatment of certain cancers, primarily liquid cancers. Nonetheless, many challenges hinder development of this therapy, such as cytokine release syndrome (CRS) and the efficacy of CAR-T treatments for solid tumors. These challenges show our inadequate understanding of this technology, particularly regarding CAR signaling, which has been less studied. To dissect CAR signaling, we designed a CAR that targets an epitope from latent membrane protein 2 A (LMP2 A) of the Epstein–Barr virus (EBV) presented on HLA*A02:01. Because of this, CAR and TCR signaling can be compared directly, allowing us to study the involvement of other signaling molecules, such as coreceptors. This comparison revealed that CAR was sufficient to bind monomeric antigens due to its high affinity but required oligomeric antigens for its activation. CAR sustained the transduced signal significantly longer, but at a lower magnitude, than did TCR. CD8 coreceptor was recruited to the CAR synapse but played a negligible role in signaling, unlike for TCR signaling. The distinct CAR signaling processes could provide explanations for clinical behavior of CAR-T therapy and suggest ways to improve the technology.

scholarly journals Regulation of proximal T cell receptor signaling and tolerance induction by deubiquitinase Usp9X

2014 ◽  
Vol 211 (10) ◽  
pp. 1947-1955 ◽  
Author(s):  
Edwina Naik ◽  
Joshua D. Webster ◽  
Jason DeVoss ◽  
Jinfeng Liu ◽  
Rowena Suriben ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tolerance Induction ◽  
Ubiquitin Ligases ◽  
Cell Receptor ◽  
Lymphoproliferative Disease ◽  
Deubiquitinating Enzymes ◽  
Tcr Signaling ◽  
Self Tolerance ◽  
A Cell

The T cell hyperproliferation and autoimmune phenotypes that manifest in mice lacking E3 ubiquitin ligases such as Cbl, ITCH, or GRAIL highlight the importance of ubiquitination for the maintenance of peripheral T cell tolerance. Less is known, however, about the deubiquitinating enzymes that regulate T cell proliferation and effector function. Here, we define a cell intrinsic role for the deubiquitinase Usp9X during proximal TCR signaling. Usp9X-deficient T cells were hypoproliferative, yet mice with T cell–specific Usp9x deletion had elevated numbers of antigen-experienced T cells and expanded PD-1 and OX40-expressing populations consistent with immune hyperactivity. Aged Usp9x KO mice developed lupus-like autoimmunity and lymphoproliferative disease, indicating that ubiquitin ligases and deubiquitinases maintain the delicate balance between effective immunity and self-tolerance.

scholarly journals CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 580-588 ◽  
Author(s):  
Kathrin Gollmer ◽  
François Asperti-Boursin ◽  
Yoshihiko Tanaka ◽  
Klaus Okkenhaug ◽  
Bart Vanhaesebroeck ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Early Time ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activation Markers

Abstract CD4+ T cells use the chemokine receptor CCR7 to home to and migrate within lymphoid tissue, where T-cell activation takes place. Using primary T-cell receptor (TCR)–transgenic (tg) CD4+ T cells, we explored the effect of CCR7 ligands, in particular CCL21, on T-cell activation. We found that the presence of CCL21 during early time points strongly increased in vitro T-cell proliferation after TCR stimulation, correlating with increased expression of early activation markers. CCL21 costimulation resulted in increased Ras- and Rac-GTP formation and enhanced phosphorylation of Akt, MEK, and ERK but not p38 or JNK. Kinase-dead PI3KδD910A/D910A or PI3Kγ-deficient TCR-tg CD4+ T cells showed similar responsiveness to CCL21 costimulation as control CD4+ T cells. Conversely, deficiency in the Rac guanine exchange factor DOCK2 significantly impaired CCL21-mediated costimulation in TCR-tg CD4+ T cells, concomitant with impaired Rac- but not Ras-GTP formation. Using lymph node slices for live monitoring of T-cell behavior and activation, we found that G protein-coupled receptor signaling was required for early CD69 expression but not for Ca2+ signaling. Our data suggest that the presence of CCL21 during early TCR signaling lowers the activation threshold through Ras- and Rac-dependent pathways leading to increased ERK phosphorylation.

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