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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.

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


  • Barnes MJ
  • Aksoylar H
  • Krebs P
  • Bourdeau T
  • Arnold CN
  • Xia Y
  • Khovananth K
  • Engel I
  • Sovath S
  • Lampe K
  • Laws E
  • Saunders A
  • Butcher GW
  • Kronenberg M
  • Steinbrecher K
  • Hildeman D
  • Grimes HL
  • Beutler B
  • Hoebe K


Journal of immunology (Baltimore, Md. : 1950)

Publication Data

April 1, 2010

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

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