Loss of T Cell and B Cell Quiescence Precedes the Onset of Microbial Flora-Dependent Wasting Disease and Intestinal Inflammation in Gimap5-Deficient Mice

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 NF-κB, MAP kinase and Akt activation occur normally. In addition, in Gimap5-deficient mice, CD4+ T cells adopt a CD44high CD62Llow CD69low 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.

Quantitative Changes in Gimap3 and Gimap5 Expression Modify Mitochondrial DNA Segregation in Mice

“…In mammals, Gimap expression appears to be restricted to hematopoietic tissues and is important for leukocyte development and survival, although the molecular basis for these functions is poorly understood (Krucken et al 2004;Nitta and Takahama 2007;Schulteis et al 2008;Barnes et al 2010;Chen et al 2011). Gimaps can be tail anchored or soluble and are structurally related to Septins, Tocs, and Dynamins (Schwefel et al 2010).…”

“…In contrast, GIMAP3 in humans appears to be a pseudogene (Krucken et al 2004). Complete loss of Gimap5 function in mice appears to be catastrophic for the hematopoietic compartment, producing a decrease of lineage-committed hematopoietic progenitors leading to a reduction of T and B lymphocytes, NK and NK T cells, altered erythropoiesis, and early lethality (Schulteis et al 2008;Barnes et al 2010;Chen et al 2011). In rats the loss of Gimap5 function is milder, as a premature termination in Gimap5 of the BioBreeding rat results only in a T-cell lymphopenia, which is a susceptibility factor for autoimmunity in this diabetic rodent model (Hornum et al 2002;MacMurray et al 2002).…”

ENU Mutagenesis in Mice - Genetic Insight into Impaired Immunity and Disease

“…Although in Gimap5 sph/sph mice no auto-antibodies can be detected, males and females developed severe colitis around 8-12 weeks of age, which was dependent on the microbiome and is CD4 + T cell driven 12 . Interestingly, inflammatory bowel disease (IBD) such as Crohn's disease, ulcerative colitis and indeterminate colitis 24, 25 manifest generally in adolescence or adulthood and they behave as complex, polygenic diseases often sharing common risk factors with other autoimmune diseases 26,27 .…”

“…Using N-ethyl-N-nitrosourea (ENU) germline mutagenesis, our laboratory previously identified Gimap5-deficient mice-designated sphinx-that exhibit reduced lymphocyte survival and develop severe colitis around 10-12 weeks of age 12 . Specifically, these mice lack NK or CD8 + T cell populations in peripheral lymphoid organs, whereas relatively normal thymocyte development occurs, including the CD4 + T cell, CD8 + T cell, and Foxp3 + regulatory T cell lineages.…”

“…Coarse mapping and sequencing of the critical region revealed a single G→T point mutation in Gimap5 to be the causal mutation. This mutation resulted in a G38C amino acid substitution in the predicted GTP-binding domain of Gimap5, destabilizing Gimap5 protein expression 12 .…”