Central T cell tolerance: Identification of tissue-restricted autoantigens in the thymus HLA-DR peptidome.
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(hi) 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.
Immunology Unit, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain; Dept of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain.
Iñaki
I
Alvarez
Immunology Unit, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain; Dept of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain.
Javier A
JA
Collado
Dept of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain; Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Institut de Recerca (VHIR), Passeig Vall d'Hebron 119-129, 08023 Barcelona, Spain.
Roger
R
Colobran
CSIC/UAB Proteomics Laboratory, IIBB-CSIC, IDIBAPS, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain.
Montserrat
M
Carrascal
Immunology Unit, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain; Dept of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain.
M Teresa
MT
Ciudad
Proteomics Laboratory, Medical Oncology Research Program, Vall d'Hebron Institut de Recerca, Barcelona, Spain.
Françesc
F
Canals
Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
Eddie A
EA
James
Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
William W
WW
Kwok
Division of Developmental Immunology, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany.
Martina
M
Gärtner
Division of Developmental Immunology, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany.
Bruno
B
Kyewski
Dept of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain; Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Institut de Recerca (VHIR), Passeig Vall d'Hebron 119-129, 08023 Barcelona, Spain.
Ricardo
R
Pujol-Borrell
Immunology Unit, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain; Dept of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain. Electronic address: dolores.jaraquemada@uab.es.
Dolores
D
Jaraquemada
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001324:Autoantigens / Q000096:biosynthesis / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D058969:Contactin 2 / Q000096:biosynthesis / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008875:Middle Aged; D017634:Self Tolerance / Q000276:immunology*; D029607:Seminal Vesicle Secretory Proteins / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis; D059467:Transcriptome; D055815:Young Adult; D000096927:AIRE Protein
D001324:Autoantigens; D058969:Contactin 2; D006684:HLA-DR Antigens; D029607:Seminal Vesicle Secretory Proteins; D014157:Transcription Factors; D000096927:AIRE Protein; C548674:CNTN2 protein, human; C424482:seminal vesicle-specific antigen
Autoantigens; Human; MHC; Peptides; Thymus; Tolerance