| Regulatory CD4+ T cells (Tregs), classically defined by expression of CD25 and the transcription factor FoxP3, are immunosuppressive sentinels that function under a variety of tissues and inflammatory milieu. Tregs express different transcriptional signatures within distinct anatomical locations. However, whether the modulation of Tregs is due to distinct anatomical locations or the type of inflammation within the tissue remains unknown. We sought to define factors that govern Treg modulation in differently inflamed skin, and in healthy and autoimmune pancreas compared to lymphoid tissues. Our data reveal three major observations in Treg accumulation and function in non-lymphoid tissues in disease and under different types of inflammation. 1) Treg accumulation in non-lymphoid tissues is drastically changed depending on the type of inflammatory milieu, which may lead to changes in Treg survival or development of autoimmune diabetes. Our skin model suggests that inflammatory changes in IL-23: IL-33 may be important in Treg accumulation and survival in tissues. In both the pancreas and skin, increased accumulation patterns correlated with a higher expression of surface CD25 on Tregs, a receptor implicated in Treg survival. Interestingly, CD25 upregulation was specific to the type of inflammatory milieu. 2) Surprisingly, gross changes in Treg transcriptional phenotype correlated more with anatomical location (skin and pancreas compared to LN) than the type of inflammation or disease state within the tissue. We identified a small number of novel transcriptional changes in Tregs associated with the diseased pancreas. 3) Inflammatory milieu directly affects Treg response to antigen in the skin. Only in inflammatory milieus that upregulated CD25 did the provision of antigen enhance local Treg proliferation. Thus, the magnitude of the Treg response in inflamed tissues is controlled at two inter-dependent levels: inflammatory signals that support the upregulation of the important Treg survival factor, CD25, and the antigen signals that drive local expansion. These results begin to reconcile some of the in vivo discrepancies about the modulation of Tregs in the non-lymphoid tissues during inflammation and autoimmune disease. Importantly, our studies may be used to advance immune therapies to govern Treg maintenance in different inflammatory and anatomical locations. |
