title: Loss of immunological tolerance in Gimap5-deficient mice is associated with loss of Foxo in CD4+ T cells.
abstract: Previously, we reported the abrogation of quiescence and reduced survival in lymphocytes from Gimap5(sph/sph) mice, an ENU germline mutant with a missense mutation in the GTPase of immunity-associated protein 5 (Gimap5). These mice showed a progressive loss of peripheral lymphocyte populations and developed spontaneous colitis, resulting in early mortality. In this study, we identify the molecular pathways that contribute to the onset of colitis in Gimap5(sph/sph) mice. We show that CD4(+) T cells become Th1/Th17 polarized and are critically important for the development of colitis. Concomitantly, regulatory T cells become reduced in frequency in the peripheral tissues, and their immunosuppressive capacity becomes impaired. Most importantly, these progressive changes in CD4(+) T cells are associated with the loss of Forkheadbox group O (Foxo)1, Foxo3, and Foxo4 expression. Our data establish a novel link between Gimap5 and Foxo expression and provide evidence for a regulatory mechanism that controls Foxo protein expression and may help to maintain immunological tolerance.
authors: Department of Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors: H Ibrahim
authors: HI
authors: Aksoylar
authors: Kristin
authors: K
authors: Lampe
authors: Michael J
authors: MJ
authors: Barnes
authors: David R
authors: DR
authors: Plas
authors: Kasper
authors: K
authors: Hoebe
mesh_terms: D000818:Animals; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019204:GTP-Binding Proteins; D005786:Gene Expression Regulation / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C534135:Gimap5 protein, mouse; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins