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cell recognition of minor histocompatibility antigens (mHags) underlies allogeneic immune responses that mediate graft-versus-host disease and the graft-versus-leukemia effect following stem cell transplantation. Many mHags derive from single amino acid polymorphisms in MHC-restricted epitopes, but our understanding of the molecular mechanisms governing mHag immunogenicity and recognition is incomplete. Here we examined antigenic presentation and T-cell recognition of HA-1, a prototypic autosomal mHag derived from single nucleotide dimorphism (HA-1(H) versus HA-1(R)) in the HMHA1 gene. The HA-1(H) peptide is restricted by HLA-A2 and is immunogenic in HA-1(R/R) into HA-1(H) transplants, while HA-1(R) has been suggested to be a \"null allele\" in terms of T cell reactivity. We found that proteasomal cleavage and TAP transport of the 2 peptides is similar and that both variants can bind to MHC. However, the His>Arg change substantially decreases the stability and affinity of HLA-A2 association, consistent with the reduced immunogenicity of the HA-1(R) variant. To understand these findings, we determined the structure of an HLA-A2-HA-1(H) complex to 1.3A resolution. Whereas His-3 is accommodated comfortably in the D pocket, incorporation of the lengthy Arg-3 is predicted to require local conformational changes. Moreover, a soluble TCR generated from HA-1(H)-specific T-cells bound HA-1(H) peptide with moderate affinity but failed to bind HA-1(R), indicating complete discrimination of HA-1 variants at the level of TCR/MHC interaction. Our results define the molecular mechanisms governing immunogenicity of HA-1, and highlight how single amino acid polymorphisms in mHags can critically affect both MHC association and TCR recognition.","bibjson":{"author":[{"initials":"S","lastname":"Nicholls","name":"Nicholls S"},{"initials":"KP","lastname":"Piper","name":"Piper KP"},{"initials":"F","lastname":"Mohammed","name":"Mohammed F"},{"initials":"TR","lastname":"Dafforn","name":"Dafforn TR"},{"initials":"S","lastname":"Tenzer","name":"Tenzer S"},{"initials":"M","lastname":"Salim","name":"Salim M"},{"initials":"P","lastname":"Mahendra","name":"Mahendra P"},{"initials":"C","lastname":"Craddock","name":"Craddock C"},{"initials":"P","lastname":"van Endert","name":"van Endert P"},{"initials":"H","lastname":"Schild","name":"Schild H"},{"initials":"M","lastname":"Cobbold","name":"Cobbold M"},{"initials":"VH","lastname":"Engelhard","name":"Engelhard VH"},{"initials":"PA","lastname":"Moss","name":"Moss PA"},{"initials":"BE","lastname":"Willcox","name":"Willcox BE"}],"identifier":[{"id":"10.1073/pnas.0900411106","type":"doi"},{"id":"19234124","type":"pubmed"}],"issue":["10"],"journal":{"iso_abbreviation":"Proc. 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