Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity

Abstract

Cytokines play a critical role in controlling the differentiation of CD4 Th cells into distinct subsets, including IL-17-producing Th17 cells. Unfortunately, the incidence of a number of autoimmune diseases, particularly those in which the IL-23/IL-17 axis has been implicated, has risen in the last several decades, suggesting that environmental factors can promote autoimmunity. Here we review the role of cytokines in Th17 differentiation, particularly the role of IL-23 in promoting the differentiation of a pathogenic subset of Th17 cells that potently induce autoimmune tissue inflammation. Moreover, we highlight emerging data that indicate that environmental factors, including the intestinal microbiota and changes in diet, can alter normal cytokine regulation with potent effects on Th17 differentiation and thus promote autoimmunity, which has strong implications for human disease.

Figure 3. Factors that alter the intestinal microenvironment can affect Th17 differentiation.

The small intestine plays an important role in promoting Th17 differentiation in vivo, and changes in dietary intake or the intestinal microbiota can alter cytokine production in that microenvironment and promote the differentiation of Th17 cells with a pathogenic phenotype. This more pro-inflammatory environment may predispose to the development of autoimmune disease. Intriguingly, many of these same factors can also predispose to the development of metabolic diseases such as type 2 diabetes. Thus, dysregulation of Th17-related cytokines may also play a role in the pathobiology of these diseases as well as in full-blown autoimmunity.

Figure 2. STAT3-dependent cytokines in autoimmunity.

Cytokines that activate STAT3, including IL-6, IL-21, and IL-23, play a critical role in promoting Th17 differentiation and have been implicated in human autoimmune disease. The signaling pathways of IL-23, IL-21, and IL-6 are shown. Genes marked in red have SNPs that have been implicated in human autoimmune diseases. Genes marked with an asterisk have targeted therapeutics either approved or in active clinical development for treatment of autoimmune disease.

Figure 1. Effector T cell subsets.

The subsets of effector Th cells are shown, along with the cytokines that drive their differentiation, lineage-defining transcription factors, and the cytokines they produce. Within the Th17 subset, two distinct subtypes of cells have been described with differing abilities to induce autoimmunity: a pathogenic subtype that produces both IL-17 and IFN-γ and a nonpathogenic subtype that produces IL-17 and IL-10.