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

• Published in: Journal of autoimmunity Vol. 60; pp. 12 - 19
• Main Authors: Alvarez, Iñaki, Collado, Javier A, Colobran, Roger, Carrascal, Montserrat, Ciudad, M. Teresa, Canals, Françesc, James, Eddie A, Kwok, William W, Gärtner, Martina, Kyewski, Bruno, Pujol-Borrell, Ricardo, Jaraquemada, Dolores
• Format: Journal Article
• Language: English
• Published: 2015
• Subjects: Allergy and Immunology; TCR; TRA; promiscuous gene expression; Xcorr; Peptides; AIRE; M-MLV RT; SVS2; liquid chromatography/mass spectrometry; MHC; major histocompatibility complex; TFA; Thymus; pGE; autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; APS-1; FDR; cross correlation score; mTEC; false discovery rate; APECED; gDNA; PSA; Human; genomic DNA; T cell receptor; cycle threshold; Tolerance; tissue-restricted antigen; Autoantigens; autoimmune regulator; autoimmune polyendocrine syndrome type 1; LC/MS; CT; seminal vesicle secretory protein 2; medullary thymic epithelial cell; trifluoroacetic acid; APC; Moloney murine leukemia virus reverse transcriptase; antigen presenting cell; dendritic cell; DC; prostate-specific antigen
• DOI: 10.1016/j.jaut.2015.03.004
• ISSN: 0896-8411

Abstract 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.