title: A structural voyage toward an understanding of the MHC-I-restricted immune response: lessons learned and much to be learned.
abstract: T cells that express clonally distributed αβ T-cell receptors (TCRs) corecognize antigenic peptides (p) bound to major histocompatibility complex class I (MHC-I) and class II molecules (MHC-II). Extensive human leukocyte antigen (HLA) polymorphism enables HLA molecules from different haplotypes to capture an array of self- and microbe-derived peptide antigens that is fundamental to adaptive immunity. T cells developing in the thymus are selected for weak binding to self-peptide-HLA complexes generating a vast repertoire of clonally distinct T cells in the periphery. Indeed, diversity within germline loci and the finally assembled TCR genes, coupled with inherent TCR cross-reactivity, enables CD8(+) T cells to survey the multitude of pHLA-I landscapes. Precisely how does the TCR ligate to pHLA-I, and how does knowledge of the detailed structural interactions inform immunobiology? A recent number of our structural studies concerning the TCR-pMHC-I axis, alongside others in the field, have provided insight into HLA-I polymorphism, pMHC-I flexibility, TCR bias, TCR polymorphism, maintenance of self-tolerance, T-cell cross-reactivity, and alloreactivity. Collectively, the data also provide an opportunity to address the structural correlates of MHC-I restriction. Here, we provide our perspective concerning these advances in the field. Although much key information has been gleaned, the structural data show that some of the key concepts surrounding the TCR-pMHC-I interaction remain controversial and unresolved.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Australia.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gras
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Turner
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001665:Binding Sites; D003429:Cross Reactions; D006680:HLA Antigens / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta