Central role of gimap5 in maintaining peripheral tolerance and T cell homeostasis in the gut

Abstract

Inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis is often precipitated by an abnormal immune response to microbiota due to host genetic aberrancies. Recent studies highlight the importance of the host genome and microflora interactions in the pathogenesis of mucosal inflammation including IBD. Specifically, genome-wide (GWAS) and also next-generation sequencing (NGS)-including whole exome or genome sequencing-have uncovered a large number of susceptibility loci that predispose to autoimmune diseases and/or the two phenotypes of IBD. In addition, the generation of "IBD-prone" animal models using both reverse and forward genetic approaches has not only helped confirm the identification of susceptibility loci but also shed critical insight into the underlying molecular and cellular pathways that drive colitis development. In this review, we summarize recent findings derived from studies involving a novel early-onset model of colitis as it develops in GTPase of immunity-associated protein 5- (Gimap5-) deficient mice. In humans, GIMAP5 has been associated with autoimmune diseases although its function is poorly defined. Here, we discuss how defects in Gimap5 function impair immunological tolerance and lymphocyte survival and ultimately drive the development of CD4(+) T cell-mediated early-onset colitis.

Figure 1

Predicted structural domains within mouse Gimap5. (a) Mouse Gimap5 is a 308-amino acid protein that contains an AIG1 domain (residues 24–227), a P-loop NTPase domain (residues 1–168), two coiled-coil domains (residues 187–221 and 239–265), and a transmembrane domain (residues 284–304). The G→C missense mutation in sphinx mice at residue 38 is indicated. (b) Schematic overview of the domain features present in the different Gimap family members.

Figure 2

Schematic representation of the key events causing colitis in Gimap5-deficient mice. Loss of Gimap5 leads to reduced survival of lymphocytes (I) including CD4⁺ T cells with remaining T cells exhibiting a characteristic LIP phenotype (CD44^high; CD62L^low) and polarization towards Th17 (II). Importantly, during the onset of CD4⁺ T cell lymphopenia, a progressive loss of full-length FoxO1, FoxO3, and FoxO4 expression is observed that correlates with a loss of T_reg induction (iTreg) and function in the gut tissue (III). The lack of T_reg immunosuppressive activity (indicated by the red X) triggers activation of CD4⁺ Th1/Th17 cells in the gut causing production of IL17 and IFNγ cytokines and subsequent infiltration of macrophages/neutrophils that further amplify intestinal inflammation and a loss of epithelial barrier function (IV) and may ultimately lead to neutrophil transepithelial migration (for an extensive review on neutrophils in IBD pathogenesis, see [133]).