How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

Significance T-cell receptor (TCR) recognition of antigenic peptides presented by major histocompatibility complex (MHC) proteins defines specificity in cellular immunity. Evidence suggests that TCRs are intrinsically biased toward MHC proteins, yet how this bias coexists alongside the considerable structural variability that is necessary for TCRs to engage different ligands has been a longstanding puzzle. By examining structural and sequence data, we found evidence that human αβ TCRs have an inherent compatibility with structural and chemical properties of MHC proteins. This compatibility leads TCRs to an intrinsic MHC bias but does not compel the formation of particular modes of binding, providing a solution to how TCRs can be MHC-biased but still structurally adaptable. How T-cell receptors (TCRs) can be intrinsically biased toward MHC proteins while simultaneously display the structural adaptability required to engage diverse ligands remains a controversial puzzle. We addressed this by examining αβ TCR sequences and structures for evidence of physicochemical compatibility with MHC proteins. We found that human TCRs are enriched in the capacity to engage a polymorphic, positively charged “hot-spot” region that is almost exclusive to the α1-helix of the common human class I MHC protein, HLA-A*0201 (HLA-A2). TCR binding necessitates hot-spot burial, yielding high energetic penalties that must be offset via complementary electrostatic interactions. Enrichment of negative charges in TCR binding loops, particularly the germ-line loops encoded by the TCR Vα and Vβ genes, provides this capacity and is correlated with restricted positioning of TCRs over HLA-A2. Notably, this enrichment is absent from antibody genes. The data suggest a built-in TCR compatibility with HLA-A2 that biases receptors toward, but does not compel, particular binding modes. Our findings provide an instructional example for how structurally pliant MHC biases can be encoded within TCRs.

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