Central T cell tolerance: Identification of tissue-restricted autoantigens in the thymus HLA-DR peptidome

Iñaki Alvarez, Javier A. Collado, Roger Colobran, Montserrat Carrascal, M. Teresa Ciudad, Françesc Canals, Eddie A. James, William W. Kwok, Martina Gärtner, Bruno Kyewski, Ricardo Pujol-Borrell, Dolores Jaraquemada

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

Abstract

© 2015 Elsevier Ltd. Promiscuous gene expression (pGE) of tissue-restricted self-antigens (TRA) in medullary thymic epithelial cells (mTECs) is in part driven by the Autoimmune Regulator gene (AIRE) and essential for self-tolerance. The link between AIRE functional mutations and multi-organ autoimmunity in human and mouse supports the role of pGE. Deep sequencing of the transcriptome revealed that mouse mTECs potentially transcribe an unprecedented range of >90% of all genes. Yet, it remains unclear to which extent these low-level transcripts are actually translated into proteins, processed and presented by thymic APCs to induce tolerance. To address this, we analyzed the HLA-DR-associated thymus peptidome. Within a large panel of peptides from abundant proteins, two TRA peptides were identified: prostate-specific semenogelin-1 (an autoantigen in autoimmune chronic prostatitis/chronic pelvic pain syndrome) and central nervous system-specific contactin-2 (an autoantigen in multiple sclerosis). Thymus expression of both genes was restricted to mTECs. SEMG1 expression was confined to mature HLA-DRhi mTECs of male and female donors and was AIRE-dependent, whereas CNTN2 was apparently AIRE-independent and was expressed by both populations of mTECs. Our findings establish a link between pGE, MHC-II peptide presentation and autoimmunity for bona fide human TRAs.
Original languageEnglish
Pages (from-to)12-19
JournalJournal of Autoimmunity
Volume60
DOIs
Publication statusPublished - 1 Jan 2015

Keywords

  • Autoantigens
  • Human
  • MHC
  • Peptides
  • Thymus
  • Tolerance

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