title: Cross-recognition of HLA DR4 alloantigen by virus-specific CD8+ T cells: a new paradigm for self-/nonself-recognition.
abstract: The ability of CD8(+) T cells to engage a diverse range of peptide-major histocompatibility complex (MHC) complexes can also lead to cross-recognition of self and nonself peptide-MHC complexes and thus directly contribute toward allograft rejection or autoimmunity. Here we present a novel form of cross-recognition by herpes virus-specific CD8(+) cytotoxic T cells that challenges the current paradigm of self/non-self recognition. Functional characterization of a human leukocyte antigen (HLA) Cw*0602-restricted cytomegalovirus-specific CD8(+) T-cell response revealed an unusual dual specificity toward a pp65 epitope and the alloantigen HLA DR4. This cross-recognition of HLA DR4 alloantigen was critically dependent on the coexpression of HLA DM and was preferentially directed toward the B-cell lineage. Furthermore, allostimulation of peripheral blood lymphocytes with HLA DRB*0401-expressing cells rapidly expanded CD8(+) T cells, which recognized the pp65 epitope in the context of HLA Cw*0602. T-cell repertoire analysis revealed 2 dominant populations expressing T-cell receptor beta variable (TRBV)4-3 or TRBV13, with cross-reactivity exclusively mediated by the TRBV13(+) clonotypes. More importantly, cross-reactive TRBV13(+) clonotypes displayed markedly lower T-cell receptor binding affinity and a distinct pattern of peptide recognition, presumably mimicking a structure presented on the HLA DR4 allotype. These results illustrate a novel mechanism whereby virus-specific CD8(+) T cells can cross-recognize HLA class II molecules and may contribute toward allograft rejection and/or autoimmunity.
authors.affiliation: Australian Centre for Vaccine Development and Tumour Immunology Laboratory, Division of Infectious Immunology, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Rist
authors.forename: Corey
authors.initials: C
authors.lastname: Smith
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Bell
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.forename: Rajiv
authors.initials: R
authors.lastname: Khanna
mesh_terms: D015551:Autoimmunity / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002461:Cell Line, Transformed; D003587:Cytomegalovirus / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology*; D015236:HLA-C Antigens / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000276:immunology*; D006801:Humans; D010455:Peptides / Q000276:immunology*; D010750:Phosphoproteins / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D014184:Transplantation, Homologous; D014763:Viral Matrix Proteins / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015236:HLA-C Antigens; D015804:HLA-DR4 Antigen; D010455:Peptides; D010750:Phosphoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa