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.
Barnes
Michael J
MJ
Department of Genetics, Scripps Research Institute, La Jolla, CA, USA.
Aksoylar
Halil
H
Krebs
Philippe
P
Bourdeau
Tristan
T
Arnold
Carrie N
CN
Xia
Yu
Y
Khovananth
Kevin
K
Engel
Isaac
I
Sovath
Sosathya
S
Lampe
Kristin
K
Laws
Eleana
E
Saunders
Amy
A
Butcher
Geoffrey W
GW
Kronenberg
Mitchell
M
Steinbrecher
Kris
K
Hildeman
David
D
Grimes
H Leighton
HL
Beutler
Bruce
B
Hoebe
Kasper
K
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D003092:Colitis / Q000235:genetics / Q000276:immunology*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000276:immunology*; D019204:GTP-Binding Proteins; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007422:Intestines / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017634:Self Tolerance / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D019282:Wasting Syndrome / Q000235:genetics / Q000276:immunology*
C534135:Gimap5 protein, mouse; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins