Central Role of Gimap5 in Maintaining Peripheral Tolerance and T Cell Homeostasis in the Gut
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 Treg induction (iTreg) and function in the gut tissue (III). The lack of Treg 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 ).
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