CD4+ T-helper 17 (Th17) signature cytokine, IL-17, mediates CD4 resistance to immune suppression

Abstract CD4+ T-helper (Th) cells are an important component of the immune system that come in several flavors, largely defined by the cytokines they produce. Important immune regulatory mechanisms mediated by CD4+ and CD8+ T-cells keep untoward effector T-cell responses in check. T-helper 17 (Th17) cells, characterized by IL-17 production, play critical roles in the body’s response to infections and cancer and in the pathogenesis of autoimmune diseases such as multiple sclerosis, psoriasis, arthritis, IBD, among others. We hypothesized that different lineages of effector Th cells would exert differential resistance to suppression. To test this, we differentiated purified naïve human CD4+ T-cells along different lineages (Th0, Th1, Th2, Th17) and tested the ability of CD8+ T-cells to suppress them. We observed that Th17 cells were highly resistant to immune suppression by CD8+ T-cells, compared to control Th0 cells. In contrast, Th1 cells were significantly more sensitive to suppression. Th17 resistance was mediated through the action of IL-17A, IL-17F and IL-17AF heterodimer through their receptors (IL-17RA and IL-17RC) on CD4+ T-cells themselves, but not through their action on CD8+ T-cells or APC. Interestingly, Th17 cells derived in different cytokine milieus showed distinct suppressive resistance, with the typical “non-pathogenic” conditions resulting in Th17 cells that were as sensitive to suppression as control Th0 cells. These studies reveal a novel function for IL-17 cytokines in a CD4-intrinsic mechanism of immune resistance that may serve as a critical target for intensive investigation and therapeutic intervention.