T helper 17 cells: discovery, function, and physiological trigger

Abstract

In the few years since their discovery, T helper 17 cells (T(H)17) have been shown to play an important role in host defense against infections, and in tissue inflammation during autoimmunity. T(H)17 cells produce IL-17, IL-21, IL-10, and IL-22 cytokines, and thus have broad effects on a variety of tissues. Notably, the requirement for the immunosuppressive cytokine TGF-beta along with the pro-inflammatory cytokine IL-6 for T(H)17 differentiation supports the intimate relationship between the T(H)17 subset and FOXP3(+) regulatory T cells. Here, we discuss current knowledge on effector functions and differentiation of the T(H)17 lineage. Furthermore, we now know of a physiological stimulus for T(H)17 differentiation: innate immune recognition of cells undergoing apoptosis as a direct result of infection induces unique development of this subset. As our knowledge of T(H)17 and T regulatory cells grows, we are building on a new framework for the understanding of effector T cell differentiation and the biology of CD4(+) T cell adaptive immune responses.

Fig. 1

Schematic representation of the transcriptional regulation of T_H17 cell differentiation. Activation of CD4⁺ T cells through the T cell receptor (TCR) in the presence of a T cell costimulatory signal results in activation and differentiation of CD4 T cells into different fates depending on the cytokine milieu. Activation of the TCR in the presence of high concentrations of TGF-β induces expression of both RORγt and FOXP3, but FOXP3 antagonizes RORγt functions leading to naïve CD4⁺ T cell differentiation into regulatory T cells (T_reg). When the pro-inflammatory cytokine IL-6 is present together with low concentrations of TGF-β, the T_H17 specific transcription factors RORγt and RORα are induced in a STAT-3-dependent manner leading to the transcriptional activation of IL-17, IL-22, and IL-23 receptor (IL-23R). Through STAT-3, IL-6 induces IL-21, which acts in a positive autocrine loop in order to amplify T_H17 cell differentiation. Indeed, IL-21 induces IL-23R expression, which imparts responsiveness to IL-23, a cytokine that maintains and expands T_H17 cells. IL-23 is also important in inducing the expression of IL-22 by T_H17 cells. Although IL-6 is dominant in vivo, in its absence and when T_reg cells are experimentally depleted, IL-21 together with TGF-β can induce T_H17 cell differentiation. Many transcription factors cooperate with RORγt and RORα in inducing maximal IL-17 and IL-22 expression. These include the aryl hydrocarbon receptor (AhR), which is also induced during T_H17 cell differentiation and inhibits FOXP3 expression, TCR-induced interferon regulatory factor IRF-4 which under T_H17 polarizing conditions upregulates RORγt expression and plays a role in IL-6 mediated downregulation of FOXP3 expression, and TCR-induced Runx1 which also upregulates RORγt expression and, together with RORγt, directs Il17 transcription. IL-27 counters the effects of TGF-β and IL-6 on differentiating CD4⁺ T cells, effectively blocking T_H17 differentiation in a STAT-1-dependent manner, and inhibiting expression of RORγt and IL-17 production. Cytokines shown in red are induced upon the initiation of T_H17 cell differentiation and are thus produced by T_H17 cells

Fig. 2

Innate immune recognition of infected apoptotic cells instructs T_H17 cell differentiation. When dendritic cells phagocytose apoptotic cells carrying TLR ligands, pathogen associated molecular patterns (PAMPs) associated with the infection engage Toll-like receptors, allowing for DC maturation and production of pro-inflammatory cytokines such as IL-6 and IL-23. The apoptotic cell element of the phagocytic cargo induces DC synthesis of the immunoregulatory cytokine TGF-β through recognition of apoptotic cell-specific molecules such as phosphatidyl serine (not shown in figure). Thus, phagocytosis of apoptotic cells by DC during an infection by DC preferentially induces differentiation of naïve CD4⁺ T cells into T_H17 cells. When DC phagocytose apoptotic cells in the absence of infection or TLR ligands, they synthesize TGF-β without pro-inflammatory cytokines, thereby promoting differentiation of tolerogenic FOXP3⁺ T_reg cells