A structure-guided approach to predict MHC-I restriction of T cell receptors for public antigens.

Peptides presented by class I major histocompatibility complex (MHC-I) proteins provide biomarkers for therapeutic targeting using T cell receptors (TCRs), TCR-mimicking antibodies (TMAs), or other engineered protein binders. Despite the extreme sequence diversity of the Human Leucocyte Antigen (HLA, the human MHC), a given TCR or TMA is restricted to recognize epitopic peptides in the context of a limited set of different HLA allotypes. Here, guided by our analysis of 96 TCR:pHLA complex structures in the Protein Data Bank (PDB), we identify TCR contact residues and classify 148 common HLA allotypes into T-cell cross-reactivity groups (T-CREGs) on the basis of their interaction surface features. Insights from our work have actionable value for resolving MHC-I restriction of TCRs, guiding therapeutic expansion of existing therapies, and informing the selection of peptide targets for forthcoming immunotherapy modalities.