Differential cytokine requirements for regulation of autoimmune gastritis and colitis by CD4(+)CD25(+) T cells.
Murine autoimmune gastritis, induced by neonatal thymectomy or the injection of CD25-depleted lymphocytes into nu/nu recipients, is characterized by an inflammatory infiltrate into the gastric mucosa, parietal cell destruction and circulating anti-parietal cell antibodies. Using RAG-2(-/-)mice as recipients, we determined that the induction of disease relies on CD4(+)CD25(-)effector cells and prevention relies on CD4(+)CD25(+)regulatory cells; neither requires participation of CD8 cells or B cells. The severity of gastritis was dependent on the cytokine repertoire of CD4(+)CD25(-)effector T cells. Recipients of IL-4(-/-)T cells developed more severe gastritis and recipients of INF-gamma(-/-)T cells developed milder disease than recipients of wildtype or IL-10(-/-)effector T cells. Gastritis did not develop in the absence of IL-12. Protection from gastritis does not require either IL-4 or IL-10 because CD4(+)CD25(+)cells from IL-4(-/-)or IL-10(-/-)mice completely abrogated the disease process. CD4(+)CD25(+)cells also protected RAG-2(-/-)recipients from colitis and inhibitory activity was partially dependent on IL-10 expression. These findings highlight the critical role of CD4(+)CD25(+)regulatory T cells in protection from several autoimmune syndromes and delineate the differential contribution of IL-10 to CD4(+)CD25(+)Treg activity in the settings of gastritis and colitis.
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, SM722, Boston, MA 02115, USA. espayer@rheuma.gu.se
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D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003092:Colitis / Q000276:immunology* / Q000517:prevention & control; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005756:Gastritis / Q000276:immunology* / Q000517:prevention & control; D007371:Interferon-gamma / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015375:Receptors, Interleukin-2 / Q000276:immunology*
D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D015375:Receptors, Interleukin-2; C064655:V(D)J recombination activating protein 2; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma