Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice
| Autor: | Michael J. Barnes, Kevin Khovananth, Philippe Krebs, Halil Aksoylar, Kasper Hoebe, Mitchell Kronenberg, Geoffrey W. Butcher, Amy Saunders, Bruce Beutler, Tristan Bourdeau, Sosathya Sovath, H. Leighton Grimes, Carrie N. Arnold, David A. Hildeman, Yu Xia, Kristin Lampe, Eleana Laws, Isaac Engel, Kris A. Steinbrecher |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Male
Adoptive cell transfer Lymphocyte T cell T-Lymphocytes Immunology Immunoblotting B-Lymphocyte Subsets Inflammation Biology Article GTP Phosphohydrolases 03 medical and health sciences Mice 0302 clinical medicine Immune system GTP-Binding Proteins T-Lymphocyte Subsets Lymphocyte homeostasis medicine Immunology and Allergy Animals Homeostasis Protein kinase B B cell 030304 developmental biology 0303 health sciences B-Lymphocytes Wasting Syndrome Liver Diseases Colitis Hematopoietic Stem Cells Mice Mutant Strains Cell biology Hematopoiesis Intestines Mice Inbred C57BL medicine.anatomical_structure Self Tolerance Female medicine.symptom 030215 immunology Signal Transduction |
| Zdroj: | Journal of Immunology |
| DOI: | 10.4049/jimmunol.0903164 |
| Popis: | 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-κB, MAP kinase and Akt activation occur normally. In addition, in Gimap5-deficient mice, CD4+ T cells adopt a CD44highCD62LlowCD69low 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|