scholarly journals K2P18.1 translates T cell receptor signals into thymic regulatory T cell development

Cell Research ◽  
2021 ◽  
Author(s):  
Tobias Ruck ◽  
Stefanie Bock ◽  
Steffen Pfeuffer ◽  
Christina B. Schroeter ◽  
Derya Cengiz ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Dominant Negative ◽  
Current Function ◽  
Cell Fate Decisions ◽  
Tract Infections ◽  
Multiple Sclerosis Patients ◽  
Treg Development

AbstractIt remains largely unclear how thymocytes translate relative differences in T cell receptor (TCR) signal strength into distinct developmental programs that drive the cell fate decisions towards conventional (Tconv) or regulatory T cells (Treg). Following TCR activation, intracellular calcium (Ca2+) is the most important second messenger, for which the potassium channel K2P18.1 is a relevant regulator. Here, we identify K2P18.1 as a central translator of the TCR signal into the thymus-derived Treg (tTreg) selection process. TCR signal was coupled to NF-κB-mediated K2P18.1 upregulation in tTreg progenitors. K2P18.1 provided the driving force for sustained Ca2+ influx that facilitated NF-κB- and NFAT-dependent expression of FoxP3, the master transcription factor for Treg development and function. Loss of K2P18.1 ion-current function induced a mild lymphoproliferative phenotype in mice, with reduced Treg numbers that led to aggravated experimental autoimmune encephalomyelitis, while a gain-of-function mutation in K2P18.1 resulted in increased Treg numbers in mice. Our findings in human thymus, recent thymic emigrants and multiple sclerosis patients with a dominant-negative missense K2P18.1 variant that is associated with poor clinical outcomes indicate that K2P18.1 also plays a role in human Treg development. Pharmacological modulation of K2P18.1 specifically modulated Treg numbers in vitro and in vivo. Finally, we identified nitroxoline as a K2P18.1 activator that led to rapid and reversible Treg increase in patients with urinary tract infections. Conclusively, our findings reveal how K2P18.1 translates TCR signals into thymic T cell fate decisions and Treg development, and provide a basis for the therapeutic utilization of Treg in several human disorders.

scholarly journals Strength of tonic T cell receptor signaling instructs T follicular helper cell–fate decisions

2020 ◽  
Vol 21 (11) ◽  
pp. 1384-1396
Author(s):  
Juliet M. Bartleson ◽  
Ashley A. Viehmann Milam ◽  
David L. Donermeyer ◽  
Stephen Horvath ◽  
Yu Xia ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Helper Cell ◽  
Cell Fate Decisions ◽  
Follicular Helper ◽  
T Cell Receptor Signaling ◽  
T Follicular Helper Cell ◽  
Cell Receptor Signaling

scholarly journals Erratum: Limited heterogeneity of rearranged T-cell receptor V α transcripts in brains of multiple sclerosis patients

Nature ◽  
1991 ◽  
Vol 353 (6339) ◽  
pp. 94-94 ◽  
Author(s):  
Jorge R. Oksenberg ◽  
Simon Stuart ◽  
Ann B. Begovich ◽  
Robert B. Bell ◽  
Henry A. Erlich ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Multiple Sclerosis Patients

scholarly journals Functional Reprogramming of the Primary Immune Response by T Cell Receptor Antagonism

2004 ◽  
Vol 200 (11) ◽  
pp. 1371-1382 ◽  
Author(s):  
Dipica Haribhai ◽  
Brandon Edwards ◽  
Mary L. Williams ◽  
Calvin B. Williams
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Effector Function ◽  
Primary Immune Response ◽  
Cell Homing ◽  
T Cell Homing ◽  
Cell Receptor Antagonism

The T cell receptor must translate modest, quantitative differences in ligand binding kinetics into the qualitatively distinct signals used to determine cell fate. Here, we use mice that express an endogenous T cell receptor (TCR) antagonist and an adoptive transfer system to examine the influence of TCR signal quality on the development of effector function. We show that activation of antigen-specific T cells in the presence of an antagonist results in a functional reprogramming of the primary immune response, marked by altered T cell homing, a failure to develop effector function, and ultimately clonal elimination by apoptosis. Importantly, antagonism does not block cell division, implying that the signals promoting clonal expansion and effector differentiation are distinct.

scholarly journals Constitutive Endocytosis and Degradation of the Pre-T Cell Receptor

2002 ◽  
Vol 195 (12) ◽  
pp. 1585-1597 ◽  
Author(s):  
Maddalena Panigada ◽  
Simona Porcellini ◽  
Eliane Barbier ◽  
Sonja Hoeflinger ◽  
Pierre-André Cazenave ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Ubiquitin Ligase ◽  
Actin Polymerization ◽  
Cell Receptor ◽  
Surface Expression ◽  
Dominant Negative ◽  
Thymic Stroma ◽  
Tcr Signals

The pre-T cell receptor (TCR) signals constitutively in the absence of putative ligands on thymic stroma and signal transduction correlates with translocation of the pre-TCR into glycolipid-enriched microdomains (rafts) in the plasma membrane. Here, we show that the pre-TCR is constitutively routed to lysosomes after reaching the cell surface. The cell-autonomous down-regulation of the pre-TCR requires activation of the src-like kinase p56lck, actin polymerization, and dynamin. Constitutive signaling and degradation represents a feature of the pre-TCR because the γδTCR expressed in the same cell line does not exhibit these features. This is also evident by the observation that the protein adaptor/ubiquitin ligase c-Cbl is phosphorylated and selectively translocated into rafts in pre-TCR– but not γδTCR-expressing cells. A role of c-Cbl–mediated ubiquitination in pre-TCR degradation is supported by the reduction of degradation through pharmacological inhibition of the proteasome and through a dominant-negative c-Cbl ubiquitin ligase as well as by increased pre-TCR surface expression on immature thymocytes in c-Cbl–deficient mice. The pre-TCR internalization contributes significantly to the low surface level of the receptor on developing T cells, and may in fact be a requirement for optimal pre-TCR function.

Limited heterogeneity of rearranged T-cell receptor Vα transcripts in brains of multiple sclerosis patients

Nature ◽  
1990 ◽  
Vol 345 (6273) ◽  
pp. 344-346 ◽  
Author(s):  
Jorge R. Oksenberg ◽  
Simon Stuart ◽  
Ann B. Begovich ◽  
Robert B. Bell ◽  
Henry A. Erlich ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Multiple Sclerosis Patients

scholarly journals Evidence That γδ versus αβ T Cell Fate Determination Is Initiated Independently of T Cell Receptor Signaling

2001 ◽  
Vol 193 (6) ◽  
pp. 689-698 ◽  
Author(s):  
Joonsoo Kang ◽  
Ariane Volkmann ◽  
David H. Raulet
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Receptor ◽  
Gene Rearrangement ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Developmental Potential ◽  
Cd8 Cells ◽  
Interleukin 7

Two types of T cells, αβ and γδ, develop in vertebrates. How these two T cell lineages arise from a common thymic T progenitor is poorly understood. Differentiation of αβ lineage T cells requires the surrogate α chain (pTα), which associates with the T cell receptor (TCR) β chain to form the pre-TCR. γδ lineage development does not appear to involve an obligatory surrogate chain, but instead requires productive rearrangement and expression of both TCR γ and δ genes. It has been proposed that the quality of signals transmitted by the pre-TCR and γδ TCR are distinct and that these “instructive” signals determine the lineage fate of an uncommitted progenitor cell. Here we show that the thymic T progenitor cells (CD25+CD44+c-kit+CD3−CD4−CD8− thymocytes, termed pro-T cells) from young adult mice that have yet to express TCRs can be subdivided based on interleukin 7 receptor (IL-7R) expression. These subsets exhibit differential potential to develop into γδ versus αβ lineage (CD4+CD8+ cells) in the thymus. Upon intrathymic injection, IL-7Rneg-lo pro-T cells generated a 13-fold higher ratio of αβ lineage to γδ lineage cells than did IL-7R+ pro-T cells. Much of this difference was due to a fivefold greater potential of IL-7R+ pro-T cells to develop into TCR-γδ T cells. Evidence indicates that this biased developmental potential is not a result of enhanced TCR-γ gene rearrangement/expression in IL-7R+ pro-T cells. These results indicate that the pro-T cells are heterogeneous in developmental potential before TCR gene rearrangement and suggest that in some precursor cells the initial lineage commitment is independent of TCR-mediated signals.

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