Inflammatory regulatory T cells in the microenvironments of ulcerative colitis and colon carcinoma

Foxp3⁺CD4⁺ regulatory T (Treg) cells are thought to express negligible levels of effector cytokines, and inhibit immune responses and inflammation. Here, we have identified a population of IL-8⁺Foxp3⁺CD4⁺ T cells in human peripheral blood, which is selectively increased in the microenvironments of ulcerative colitis and colon carcinoma. Phenotypically, this population is minimally overlapping with IL-17⁺Foxp3⁺CD4⁺ T cells, and is different from IL-8⁻Foxp3⁺CD4⁺ T cells in the same microenvironment. 40–60% of IL-8⁺Foxp3⁺CD4⁺ T cells exhibit naive phenotype and express CD127, whereas IL-8⁻Foxp3⁺CD4⁺ cells are basically memory T cells and express minimal CD127. The levels of CXCR5 expression are higher in IL-8⁺Foxp3⁺ cells than in IL-8⁻Foxp3⁺ cells. IL-2 and TGFβ induce IL-8⁺Foxp3⁺ T cells. Exogenous Foxp3 expression promotes IL-8⁺Foxp3⁺ T cells and inhibits effector cytokine IFNγ and IL-2 expression. Furthermore, Foxp3 binds to IL-8 proximal promoter and increases its activity. Functionally, IL-8⁺Foxp3⁺ T cells inhibit T cell proliferation and effector cytokine production, but stimulate inflammatory cytokine production in the colon tissues, and promote neutrophil trafficking through IL-8. Thus, IL-8⁺Foxp3⁺ cells may be an “inflammatory” Treg subset, and possess inflammatory and immunosuppressive dual biological activities. Given their dual roles and localization, these cells may be in a unique position to support tumor initiation and development in human chronic inflammatory environment.