When worlds collide: Th17 and Treg cells in cancer and autoimmunity

Abstract

The balance between Th17 cells and regulatory T cells (Tregs) has emerged as a prominent factor in regulating autoimmunity and cancer. Th17 cells are vital for host defense against pathogens but have also been implicated in causing autoimmune disorders and cancer, though their role in carcinogenesis is less well understood. Tregs are required for self-tolerance and defense against autoimmunity and often correlate with cancer progression. This review addresses the importance of a functional homeostasis between these two subsets in health and the consequences of its disruption when these forces collide in disease. Importantly, we discuss the ability of Th17 cells to mediate cancer regression in immunotherapy, including adoptive transfer and checkpoint blockade therapy, and the therapeutic possibilities of purposefully offsetting the Th17/Treg balance to treat patients with cancer as well as those with autoimmune diseases.

Keywords: Th17; Treg; autoimmunity; cancer; immunotherapy.

Fig. 1. CD4⁺ cell differentiation and effector function.

CD4⁺ T cells differentiate based on the presence of various cytokines. Under the influence of IL-2 and TGF-β, Treg cells develop and express transcription factors STAT5 and Foxp3 and cytokines TGF-β and IL-10. IL-12 influences Th1 cell development and promotes immunity upon the presence of IFN-γ, STAT4, T-bet, and LTα. Th2 cell differentiation is induced by IL-4, during which cytokine release may manifest in allergies or asthma. Th17 cell development occurs following the influence of TGF-β, IL-6, and IL-21. IL-1β and IL-23 maintain Th17 cell stabilization during clonal expansion. Upon differentiation, Th17 cells are most commonly classified by their expression of RORγt and STAT3. Th9, Th22, and Tfh cells have been most recently described, and transcription factors controlling their differentiation remain under debate

Fig. 2. Cytokines induce functional plasticity of Th17s and Tregs.

Both Th17 cells and Tregs exhibit the ability to acquire characteristics of other helper subsets. The presence of Th17-type cytokines IL-1B and IL-6 can generate Treg-producing IL-17. The ability of Th17 to differentiate into a Treg-like phenotype is less well described at this time. Similarly, a Th17 cell reactivated in the presence of IL-12 generates an ex-Th17 or non-classical Th1 cell with self-renewing abilities compared to a classical Th1 cell that progressively differentiates into senescence