Conserved Biophysical Compatibility Among the Highly Variable Germline-Encoded Regions Shapes TCR-MHC Interactions

T cells are critically important components of the adaptive immune system primarily responsible for identifying and responding to pathogenic challenges. This antigen recognition is based on the interaction between membrane-bound T cell receptors (TCRs) and peptides presented on major histocompatibility complex (MHC) molecules. The formation of the TCR-peptide-MHC complex (TCR-pMHC) can be broken into two types of interactions, one between the hypervariable TCR CDR3α/β loops and the presented peptide and the second between germline-encoded regions of the TCR and MHC. Experimental investigation of the latter interaction, mediated by the CDR1 and CDR2 loops of αβ TCRs, has been historically difficult. To address this prominent gap in our knowledge, we analyzed every possible germline-encoded TCR-MHC contact in humans, thereby generating the first comprehensive characterization of these antigen-independent interactions. Our analysis shows that germline-encoded TCR-MHC interactions that are conserved at the sequence level are rare due to the exceptional diversity of the TCR CDR1 and CDR2 loops. Instead, binding properties such as the docking orientation are defined by regions of biophysical compatibility between these loops and the MHC surface. We further find that TCR genes which encode CDR loops with low potential to interact with MHC are over-represented in autoimmune contexts.