The TCR Ca Domain Regulates Responses to Self-pMHC Class II

T cells play a central role in adaptive immunity by recognizing peptide Ags presented by MHC molecules (pMHC) via their clonotypic TCRs. abTCRs are heterodimers, consisting of TCRa and TCRb subunits that are composed of variable (Va, Vb) and constant (Ca, Cb) domains. Whereas the Va, Vb, and Cb domains adopt typical Ig folds in the extracellular space, the Ca domain lacks a top b sheet and instead has two loosely associated top strands (C- and F-strands) on its surface. Previous results suggest that this unique Ig-like fold mediates homotypic TCR interactions and influences signaling in vitro. To better understand why evolution has selected this unique structure, we asked, what is the fitness cost for development and function of mouse CD4⁺ T cells bearing a mutation in the Ca C-strand? In both TCR retrogenic and transgenic mice we observed increased single-positive thymocytes bearing mutant TCRs compared with those expressing wild-type TCRs. Furthermore, our analysis of mutant TCR transgenic mice revealed an increase in naive CD4⁺ T cells experiencing strong tonic TCR signals, increased homeostatic survival, and increased recruitment of responders to cognate pMHC class II upon immunization compared with the wild-type. The mutation did not, however, overtly impact CD4⁺ T cell proliferation or differentiation after immunization. We interpret these data as evidence that the unique Ca domain has evolved to fine-tune TCR signaling, particularly in response to weak interactions with self-pMHC class II.