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Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice.

http://www.ncbi.nlm.nih.gov/pubmed/20190135

Homeostatic control of the immune system involves mechanisms that ensure the self-tolerance, survival and quiescence of hematopoietic-derived cells. In this study, we demonstrate that the GTPase of immunity associated protein (Gimap)5 regulates these processes in lymphocytes and hematopoietic progenitor cells. As a consequence of a recessive N-ethyl-N-nitrosourea-induced germline mutation in the P-loop of Gimap5, lymphopenia, hepatic extramedullary hematopoiesis, weight loss, and intestinal inflammation occur in homozygous mutant mice. Irradiated fetal liver chimeric mice reconstituted with Gimap5-deficient cells lose weight and become lymphopenic, demonstrating a hematopoietic cell-intrinsic function for Gimap5. Although Gimap5-deficient CD4(+) T cells and B cells appear to undergo normal development, they fail to proliferate upon Ag-receptor stimulation although NF-kappaB, MAP kinase and Akt activation occur normally. In addition, in Gimap5-deficient mice, CD4(+) T cells adopt a CD44(high)CD62L(low)CD69(low) phenotype and show reduced IL-7ralpha expression, and T-dependent and T-independent B cell responses are abrogated. Thus, Gimap5-deficiency affects a noncanonical signaling pathway required for Ag-receptor-induced proliferation and lymphocyte quiescence. Antibiotic-treatment or the adoptive transfer of Rag-sufficient splenocytes ameliorates intestinal inflammation and weight loss, suggesting that immune responses triggered by microbial flora causes the morbidity in Gimap5-deficient mice. These data establish Gimap5 as a key regulator of hematopoietic integrity and lymphocyte homeostasis.

Pubmed ID: 20190135 RIS Download

Mesh terms: Animals | B-Lymphocyte Subsets | B-Lymphocytes | Colitis | Female | GTP Phosphohydrolases | Hematopoiesis | Hematopoietic Stem Cells | Homeostasis | Immunoblotting | Inflammation | Intestines | Liver Diseases | Male | Mice | Mice, Inbred C57BL | Mice, Mutant Strains | Self Tolerance | Signal Transduction | T-Lymphocyte Subsets | T-Lymphocytes | Wasting Syndrome

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Associated grants

  • Agency: NCI NIH HHS, Id: 1R21CA133649-01
  • Agency: NIAID NIH HHS, Id: 5P01AI070167
  • Agency: NIDDK NIH HHS, Id: P30 DK078392
  • Agency: NCI NIH HHS, Id: R21 CA133649
  • Agency: NIAID NIH HHS, Id: R37 AI71922

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