TCRγ constant usage tunes human γδ T cell antigen sensitivity, thymic programming, and peripheral function

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.