TY - JOUR
T1 - Molecular and functional bases of self-antigen recognition in long-term persistent melanocyte-specific CD8+ T cells in one vitiligo patient
AU - Mantovani, Stefania
AU - Garbelli, Silvia
AU - Palermo, Belinda
AU - Campanelli, Rita
AU - Brazzelli, Valeria
AU - Borroni, Giovanni
AU - Martinetti, Myriam
AU - Benvenuto, Federica
AU - Merlini, Giampaolo
AU - Della Cuna, Gioacchino Robustelli
AU - Rivoltini, Licia
AU - Giachino, Claudia
PY - 2003/8/1
Y1 - 2003/8/1
N2 - 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 α chain rearrangement in 100% of clones and a conserved amino acid sequence was found in the β chain complementarity determining region 3 of various high affinity cells. We suggest that the conserved α chain confers self-antigen recognition, necessary for intrathymic selection and peripheral homeostasis, to many synonymous T cell receptors, whereas the β 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.
AB - 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 α chain rearrangement in 100% of clones and a conserved amino acid sequence was found in the β chain complementarity determining region 3 of various high affinity cells. We suggest that the conserved α chain confers self-antigen recognition, necessary for intrathymic selection and peripheral homeostasis, to many synonymous T cell receptors, whereas the β 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.
KW - Cytotoxic T lymphocytes
KW - Human
KW - MART-1
KW - Melan-A
KW - T cell receptor
KW - Vitiligo
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U2 - 10.1046/j.1523-1747.2003.12368.x
DO - 10.1046/j.1523-1747.2003.12368.x
M3 - Article
C2 - 12880423
AN - SCOPUS:0041621583
VL - 121
SP - 308
EP - 314
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
SN - 0022-202X
IS - 2
ER -