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

Peptides presented by major histocompatibility complex class I (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 leukocyte 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 alleles. Here, guided by our analysis of 98 TCR:pHLA complex structures, we identify TCR contact residues and classify 148 common HLA alleles into T cell cross-reactivity groups (T-CREGs) on the basis of their presented surface features. Insights from our work have actionable value for predicting MHC-I restriction of TCRs, guiding therapeutic expansion of existing TCR-based approaches and informing the selection of peptide targets for the development of new therapeutics.