Molecular and functional bases of self-antigen recognition in long-term persistent melanocyte-specific CD8+ T cells in one vitiligo patient

Stefania Mantovani, Silvia Garbelli, Belinda Palermo, Rita Campanelli, Valeria Brazzelli, Giovanni Borroni, Myriam Martinetti, Federica Benvenuto, Giampaolo Merlini, Gioacchino Robustelli Della Cuna, Licia Rivoltini, Claudia Giachino

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Pages (from-to)308-314
Number of pages7
JournalJournal of Investigative Dermatology
Volume121
Issue number2
DOIs
Publication statusPublished - Aug 1 2003

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Keywords

  • Cytotoxic T lymphocytes
  • Human
  • MART-1
  • Melan-A
  • T cell receptor
  • Vitiligo

ASJC Scopus subject areas

  • Dermatology

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