Central Role of Gimap5 in Maintaining Peripheral Tolerance and T Cell Homeostasis in the Gut

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 (; ) 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]).