title: Distinct roles of T-cell lymphopenia and the microbial flora for gastrointestinal and CNS autoimmunity.
abstract: T-cell lymphopenia is a major risk factor for autoimmunity. Here we describe congenic Lewis (LEW) rats with a loss-of-function mutation in the Gimap5 gene, leading to a 92% reduction in peripheral T-cell numbers. Gimap5-deficient LEW rats developed eosinophilic autoimmune gastroenteritis accompanied by a 40-fold increase in IgE serum levels. This phenotype was ameliorated by antibiotic treatment, indicating a critical role of the microbial flora in the development of inflammatory bowel disease. Interestingly, Gimap5-deficient LEW rats showed strongly aggravated experimental autoimmune encephalomyelitis (EAE) after immunization with guinea pig myelin basic protein. This phenotype, however, persisted after antibiosis, confirming that the enhanced CNS autoimmune response in T-cell lymphopenic Gimap5-deficient LEW rats was unrelated to the composition of the microbial flora. Rather, it seems that it was caused by the 7-fold increase in the percentage of activated T cells producing IL-17 and IFN-γ, and the skewed T-cell receptor (TCR) repertoire, both of which were the result of T-cell lymphopenia and not affected by antibiosis. This notion was supported by the observation that adoptive T-cell transfer corrected the TCR repertoire and improved EAE. Collectively, our findings confirm a critical albeit differential role of T-cell lymphopenia in the susceptibility to organ-specific autoimmune responses.-Fischer, H. J., Witte, A.-K., Walter, L., Gröne, H.-J., van den Brandt, J., Reichardt, H. M. Distinct roles of T-cell lymphopenia and the microbial flora for gastrointestinal and CNS autoimmunity.
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany;
authors.forename: Henrike J
authors.initials: HJ
authors.lastname: Fischer
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany;
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Witte
authors.affiliation: Primate Genetics Laboratory, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany; and.
authors.forename: Lutz
authors.initials: L
authors.lastname: Walter
authors.affiliation: Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany;
authors.forename: Jens
authors.initials: J
authors.lastname: van den Brandt
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany; hreichardt@med.uni-goettingen.de.
authors.forename: Holger M
authors.initials: HM
authors.lastname: Reichardt
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism / Q000382:microbiology*; D002490:Central Nervous System / Q000276:immunology / Q000382:microbiology*; D002493:Central Nervous System Diseases / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005759:Gastroenteritis / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D041981:Gastrointestinal Tract / Q000276:immunology* / Q000382:microbiology; D005786:Gene Expression Regulation / Q000276:immunology; D008231:Lymphopenia; D017354:Point Mutation; D051381:Rats; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D019204:GTP-Binding Proteins; C494977:Gimap5 protein, rat
keywords: T-cell receptor repertoire; T-cell transfer; eosinophilic bowel disease; experimental autoimmune encephalomyelitis; rat