The structure of the human allo‐ligand HLA‐B*3501 in complex with a cytochrome p450 peptide: Steric hindrance influences TCR allo‐recognition

AbstractVirus‐specific T cell populations have been implicated in allo‐recognition. The subdominant T cell receptor JL12 recognizes both HLA‐B*0801 presenting the Epstein–Barr virus‐derived peptide FLRGRAYGL and also HLA‐B*3501 presenting the cytochrome p450 self peptide KPIVVLHGY. This cross‐reactivity could promote the rejection of HLA‐B*3501‐positive cells in Epstein–Barr virus‐exposed HLA‐B*0801 recipients. LC13, the dominant TCR against the HLA‐B*0801:FLRGRAYGL complex, fails to recognize HLA‐B*3501:KPIVVLHGY. We report the 1.75‐Angstrom resolution crystal structure of the human allo‐ligand HLA‐B*3501:KPIVVLHGY. Similarities between this structure and that of HLA‐B*0801:FLRGRAYGL may facilitate cross‐recognition by JL12. Moreover, the elevated peptide position in HLA‐B*3501:KPIVVLHGY would provide steric hindrance to LC13, preventing it from interacting in the manner in which it interacts with HLA‐B*0801:FLRGRAYGL. These findings are relevant to understanding the basis of T cell cross‐reactivity in allo‐recognition, optimal transplant donor‐recipient matching and developing specific molecular inhibitors of allo‐recognition.