The role of IL-17-producing Foxp3+ CD4+ T cells in inflammatory bowel disease and colon cancer

Abstract

The intestinal epithelium and underlying lamina propria contain T cells that play important roles in maintaining colonic homeostasis. These T cells mediate substantial and specific regulation to ensure that pathogenic microorganisms are eliminated while commensal bacteria are tolerated. There is considerable evidence supporting the notion that the altered ratio between Foxp3(+)CD4(+) T regulatory cells and T effector cells in the colonic microenvironment might contribute to the initiation and progression of inflammation and eventually development of colon cancer. Recent findings on the heterogeneity and plasticity of T regulatory cells, such as the identification of IL-17(+)Foxp3(+)CD4(+) and the RORγt(+)Foxp3(+)CD4(+) subsets, in patients with colorectal inflammation and cancer have provided a new twist in our understanding of the pathogenesis of colonic diseases. Phenotypic and functional properties of IL-17-producing Foxp3(+)CD4(+) T cells as well as the significant implications of these cells in the initiation and progression of colorectal diseases are discussed in this review.

Keywords: Colon cancer; IL-17; Inflammatory bowel disease; RORγt; T regulatory cells; Th17.

Figure 1. Induction of T_Reg cell mediated gut immune tolerance

In the steady state, gut immune tolerance is induced and maintained by a variety of mechanisms, which regulate the differentiation and activation of T_Reg cells. Some commensal bacteria can induce the differentiation of CD4⁺ T cells into T_Reg cells in a TLRs dependent manner. Clostridium spp. can induce generation of IL-10 producing T_Reg cells via epithelial cell-derived TGF-β, whereas Bacteroides fraglilis can induce IL-10 producing T_Reg cells via polysaccharide A (PSA). CD103⁺DC can also induce T_Reg cells through their ability to produce retinoic acid and TGF-β. T_Reg cells act on macrophage and myeloid cells to inhibit their ability to produce colitogenic cytokines including IL-12p40, Il-6 and IL-23, which are required for the differentiation of CD4⁺ T cells into Th1 and Th17 cells. Both Th1 and Th17 cells are associated with initiation and progression of IBD and colon cancer. T_Reg cells suppress inflammatory responses mainly through production of anti-inflammatory cytokines TGF-β and more importantly IL-10.

Figure 2. Opposing effects of Foxp3⁺T_Reg and RORγt⁺Foxp3⁺T_Reg cells in the development of IBD and colon cancer

Foxp3⁺ T_Reg cells suppress both T-cell mediated anti-tumor immune response and inflammatory response at least in part by secretion of IL-10 and TGF-β in response to TCR-mediated stimulation. Given their ability to suppress inflammatory processes, Foxp3⁺ T_Reg cells play an important role in controlling and suppressing the pathogenesis of IBD and subsequently the development of colon cancer. However, in the context of an inflammatory milieu, Foxp3⁺ T_Reg cells are able to express RORγt and have the potential to express and secrete IL-17. The resultant RORγt⁺Foxp3⁺T_Reg cells display potent suppressive activity on T-cell mediated immune responses, whereas their antiinflammatory function is compromised. As a consequence, RORγt⁺Foxp3⁺ T_Reg cells are unable to control inflammation and rather promote instead of suppressing the development of colon cancer.