| Title: |
TCRγ constant usage tunes human γδ T cell antigen sensitivity, thymic programming, and peripheral function. |
| Authors: |
Viswanathan, Mayuri; Castro, Caitlin D.; Broughton, Augusta E.; Ramesh, Amrita; Asby, Nicholas; Bergquist, Alejandra; Kaiser, Caroline; Luna, Alexander; Huang, Jun; Bissonnette, Marc; Koh, Andrew; Hibino, Narutoshi; Schoettler, Nathan; Sperling, Anne; Adams, Erin J. |
| Source: |
Science Immunology; 2026, Vol. 11 Issue 116, p1-11, 11p |
| Subject Terms: |
T cell receptors; T cells; Cytotoxic T cells; Colon tumors |
| Abstract: |
Activation in T cells through their antigen receptors has been closely tied to the strength of recognition of their cognate antigens, dictated by the variable complementarity-determining region loops. We show that, in the human gamma delta (γδ) T cell receptors (TCRs), the gamma constant domains modulate activation intensity independent of variable region antigen recognition. Using single-cell RNA sequencing data, we demonstrate that Cγ usage in vivo corresponds with distinct phenotypes, with cells using Cγ1 having a more differentiated cytotoxic effector phenotype in the thymus and higher granzyme expression in peripheral tissues. TCRs with Cγ1 are also selectively expanded in colorectal tumors. Cγ2 usage is correlated with naïve phenotypes in development and with inhibition and wound healing in the periphery. We propose that the modulation of activation using Cγ1 or Cγ2 translates to differences in γδ T cell phenotype and clonal expansion throughout its life span, providing human γδ T cells another "dial" to modulate their function. Editor's summary: Although γδ T cells play important roles in both immune and nonimmune processes, our understanding of how T cell receptors (TCRs) inform their dynamics is more limited than for αβ T cells. Viswanathan et al. analyzed how the two forms of the γ chain constant domain (Cγ1 and Cγ2) contribute to human γδ T cell function. Cγ1+ and Cγ2+ T cells exhibited distinct thymic temporal dynamics, and both comprised part of the γδ T cell repertoire in peripheral blood and normal and tumor colon tissue. Cγ1+ T cells, whose TCRs produce greater signal strength, were expanded in colorectal tumors and showed a more differentiated cytotoxic phenotype. By contrast, the more naïve-like Cγ2+ T cells expressed regulatory and wound-healing genes. Thus, usage of TCRγ constant chain may be another way in which the host can fine-tune its immune responses. —Seth Thomas Scanlon [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |