title: Molecular and functional bases of self-antigen recognition in long-term persistent melanocyte-specific CD8+ T cells in one vitiligo patient.
abstract: Vitiligo patients possess high frequencies of circulating CD8+ T lymphocytes specific for the melanocyte differentiation antigen Melan-A/MART-1. These self-specific T cells exhibit intact functional properties and their T cell receptors are selected for a narrow range of high affinities of antigen recognition, suggesting their important role in the pathogenesis of vitiligo. In order to understand the molecular base for this unexpected, optimal T cell receptor recognition of a self-antigen, a tetramer-guided ex vivo analysis of the T cell receptor repertoire specific for the Melan-A antigen in a patient affected by vitiligo is reported. All T cell receptors sequenced corresponded to different clonotypes, excluding extensive clonal expansions and revealing a large repertoire of circulating Melan-A-specific T lymphocytes. A certain degree of T cell receptor structural conservation was noticed, however, as a single AV segment contributed to the alpha chain rearrangement in 100% of clones and a conserved amino acid sequence was found in the beta chain complementarity determining region 3 of various high affinity cells. We suggest that the conserved alpha chain confers self-antigen recognition, necessary for intrathymic selection and peripheral homeostasis, to many synonymous T cell receptors, whereas the beta chain fine tunes the T cell receptor affinity of the specific cells. In addition, we demonstrate that many high avidity T cell clones from this patient were capable of specifically lysing normal, HLA-matched melanocytes. These autoreactive clones persisted for more than 3 y in the patient's peripheral blood. These data, together with the skin-homing potential of the clones, directly point to the in vivo pathogenic role of melanocyte-specific cytotoxic T lymphocytes in vitiligo.
authors.affiliation: Experimental Immunology Laboratory, IRCCS Maugeri Foundation, Pavia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mantovani
authors.forename: Silvia
authors.initials: S
authors.lastname: Garbelli
authors.forename: Belinda
authors.initials: B
authors.lastname: Palermo
authors.forename: Rita
authors.initials: R
authors.lastname: Campanelli
authors.forename: Valeria
authors.initials: V
authors.lastname: Brazzelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Borroni
authors.forename: Myriam
authors.initials: M
authors.lastname: Martinetti
authors.forename: Federica
authors.initials: F
authors.lastname: Benvenuto
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.forename: Gioacchino Robustelli
authors.initials: GR
authors.lastname: della Cuna
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
authors.forename: Claudia
authors.initials: C
authors.lastname: Giachino
mesh_terms: D000951:Antigens, Neoplasm; D001324:Autoantigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells; D005260:Female; D015234:HLA-A Antigens / Q000032:analysis; D015789:HLA-A2 Antigen; D006801:Humans; D058965:MART-1 Antigen; D008544:Melanocytes / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D014820:Vitiligo / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell