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

Homeostatic control of the immune system involves mechanisms that ensure the self-tolerance, survival and quiescence of hema-topoietic-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-kB, 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-7ra 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. M any layers of regulation ensure homeostatic control of the immune system during development and throughout life. In fetal and neonatal mice, hematopoietic stem cells (HSCs) and precursor cells migrate from the fetal liver to the bone marrow and thymus (1). Thereafter, maintenance of the HSC niche involves both cell-extrinsic and cell-intrinsic mechanisms in which responsiveness to growth factors, cell cycle control, and breakdown of metabolic by-products are essential (2). When these processes occur normally, the many diverse lineages of hematopoietic cells are continually generated in the bone marrow and thymus. Given their potential to undergo clonal expansion and long-term survival, additional checkpoints are needed to limit the survival of self-reactive T cells and B cells (3). In T cells, these checkpoints include the induction of apoptosis in thymocytes that recognize self-Ags with high affinity (negative selection) (4) and the mitigation of inappropriate immune responses by regulatory T cells (5). The availability of common–g-chain cytokines governs the size and composition of the T cell niche (6–8). Notably, IL-2, IL-7, and IL-15 promote T cell survival by modulating the expression of Bcl-2–family member proteins. Somewhat paradoxically, mutations or conditions that partially impair T cell …