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Title

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

AuthorsÁlvarez, Iñaki; Carrascal, Montserrat ; Jaraquemada, Dolores
KeywordsPeptides
Autoantigens
Tolerance
Thymus
Human
MHC
Issue Date1-Jun-2015
PublisherAcademic Press
CitationJournal of Autoimmunity 60: 12-19 (2015)
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-DR<sup>hi</sup> 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.
DescriptionIñaki Álvarez et al.
Publisher version (URL)http://dx.doi.org/10.1016/j.jaut.2015.03.004
URIhttp://hdl.handle.net/10261/124564
DOI10.1016/j.jaut.2015.03.004
Identifiersdoi: 10.1016/j.jaut.2015.03.004
issn: 1095-9157
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