| Popis: |
T-cells play a central role in adaptive immunity by recognizing peptide-antigens presented in MHC molecules (pMHC) via their clonotypic T-cell receptors (TCRs). αβTCRs are heterodimers, consisting of TCRα and TCRβ subunits that are composed of variable (Vα, Vβ) and constant (Cα, Cβ) domains. While the Vα, Vβ, and Cβ domains adopt typical immunoglobulin (Ig) folds in the extracellular space, the Cα domain lacks a top β 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 signalingin vitro. To better understand why evolution has selected this unique structure, we asked: what is the fitness cost for development and function of CD4+T cells bearing a mutation in the Cα 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 pMHCII upon immunization, compared to 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 Cα domain has evolved to fine-tune TCR signaling, particularly in response to weak interactions with self-pMHCII. |
