Previous work described an essential role for 3-phosphoinositide-dependent protein kinase 1 (PDK1) in transducing activatory signals from the co-receptor CD28 during CD4+ T cell activation. Surprisingly, the authors found that transgenic mice with a CD4+ T cell-specific deletion of PDK1 developed spontaneous colitis, despite showing defective CD4+ T cell activation. By characterizing colonic leukocyte populations, they found that γδ T cells (but not αβ T cell or B cell populations) were markedly increased in the colonic epithelium of mice with PDK1-deficient CD4+ T cells. In particular, an increased proportion of interleukin-17 (IL-17)-producing γδ T cells was found in the colons of the transgenic mice compared with wild-type mice, suggesting that these γδ T cells contributed to disease development. To explore this further, the authors crossed mice with PDK1-deficient CD4+ T cells with animals lacking γδ T cells and found that these double-deficient mice no longer developed colitis. Treatment with antibiotics also prevented disease in mice with PDK1-deficient CD4+ T cells. These findings confirmed that γδ T cells are required for colitis development in this model and suggested that γδ T cells are activated in response to the commensal microbiota.
As the transgenic mice also lacked PDK1 expression in CD4+ TReg cells, the authors next explored whether colitis in these animals resulted from a TReg cell defect. In mice with PDK1-deficient CD4+ T cells, forkhead box P3 (FOXP3)+ TReg cells developed normally and were only slightly reduced in number in the periphery. However, in contrast to wild-type TReg cells, PDK1-deficient TReg cells failed to upregulate various anti-inflammatory cytokines, including IL-10, following activation with CD3- and CD28-specific antibodies, and were only weakly suppressive in vitro. Furthermore, in the classic T cell transfer model of colitis, PDK1-deficient TReg cells could not prevent disease development.
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