title: IL-7 dysregulation and loss of CD8+ T cell homeostasis in the monogenic human disease autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
abstract: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autoimmune disease that is caused by mutations in the AIRE gene. Murine studies have linked AIRE to thymocyte selection and peripheral deletional tolerance, but the pathogenesis of the human disease remains unclear. In this study, we show that APECED patients have elevated IL-7 levels and a drastically decreased expression of IL-7R on CD8(+) T cells. This is associated with increased proliferation and a decreased expression of the negative TCR regulator CD5 in the CD45RO(-) subset. The CD45RO(-) cells also display oligoclonal expansions, decreased expression of the lymph node homing factors CCR7 and CD62L, and increased expression of perforin, consistent with the accumulation of highly differentiated effector cells. The CD45RO(-)CCR7(+)CD8(+) population of cells with markers characteristic of naive phenotype is also skewed, as shown by decreased expression of CD5 and increased expression of perforin. The putative CD31(+) recent thymic emigrant population is likewise affected. These data are consistent with IL-7 dysregulation inducing a decreased threshold of TCR signaling and self-antigen-driven proliferation, probably in synergy with the failed thymic selection. The resultant loss of CD8(+) T cell homeostasis is likely to play a significant role in the pathogenesis of APECED. Our findings may also hold lessons for other diseases in which the IL-7-IL-7R pathway has emerged as a risk factor.
authors.affiliation: Department of Immunology, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Sini M
authors.initials: SM
authors.lastname: Laakso
authors.forename: Eliisa
authors.initials: E
authors.lastname: Kekäläinen
authors.forename: Laura H
authors.initials: LH
authors.lastname: Rossi
authors.forename: Tuisku-Tuulia
authors.initials: TT
authors.lastname: Laurinolli
authors.forename: Helga
authors.initials: H
authors.lastname: Mannerström
authors.forename: Nelli
authors.initials: N
authors.lastname: Heikkilä
authors.forename: Anni
authors.initials: A
authors.lastname: Lehtoviita
authors.forename: Jaakko
authors.initials: J
authors.lastname: Perheentupa
authors.forename: Hanna
authors.initials: H
authors.lastname: Jarva
authors.forename: T Petteri
authors.initials: TP
authors.lastname: Arstila
mesh_terms: D000328:Adult; D000818:Animals; D000943:Antigens, Differentiation / Q000097:blood / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D015851:Interleukin-7 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D016884:Polyendocrinopathies, Autoimmune / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000097:blood / Q000235:genetics / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000096927:AIRE Protein
chemical_list: D000943:Antigens, Differentiation; D015851:Interleukin-7; D011948:Receptors, Antigen, T-Cell; D020395:Receptors, Interleukin-7; D014157:Transcription Factors; D000096927:AIRE Protein; C508605:IL7 protein, human