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

Michael J. Barnes, Halil Aksoylar, Philippe Krebs, Tristan Bourdeau, Carrie N. Arnold, Yu Xia, Kevin Khovananth, Isaac Engel, Sosathya Sovath, Kristin Lampe, Eleana Laws, Amy Saunders, Geoffrey W. Butcher, Mitchell Kronenberg, Kris Steinbrecher, David Hildeman, H. Leighton Grimes, Bruce Beutler, Kasper Hoebe

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

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 NFκB, MAP kinase and Akt activation occur normally. In addition, in Gimap5-deficient mice, CD4+ T cells adopt a CD44highCD62Llow CD69 low phenotype and show reduced IL-7rα 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.

Original languageEnglish (US)
Pages (from-to)3743-3754
Number of pages12
JournalJournal of Immunology
Volume184
Issue number7
DOIs
StatePublished - Apr 1 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Barnes, M. J., Aksoylar, H., Krebs, P., Bourdeau, T., Arnold, C. N., Xia, Y., Khovananth, K., Engel, I., Sovath, S., Lampe, K., Laws, E., Saunders, A., Butcher, G. W., Kronenberg, M., Steinbrecher, K., Hildeman, D., Grimes, H. L., Beutler, B., & Hoebe, K. (2010). Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice. Journal of Immunology, 184(7), 3743-3754. https://doi.org/10.4049/jimmunol.0903164