Mechanisms controlling Th17 cytokine expression and host defense

Abstract

Th17 cells contribute to mucosal immunity by stimulating epithelial cells to induce antimicrobial peptides, granulopoiesis, neutrophil recruitment, and tissue repair. Recent studies have identified important roles for commensal microbiota and Ahr ligands in stabilizing Th17 gene expression in vivo, linking environmental cues to CD4 T cell polarization. Epigenetic changes that occur during the transition from naïve to effector Th17 cells increase the accessibility of il17a, il17f, and il22 loci to transcription factors. In addition, Th17 cells maintain the potential for expressing T-bet, Foxp3, or GATA-binding protein-3, explaining their plastic nature under various cytokine microenvironments. Although CD4 T cells are major sources of IL-17 and IL-22, innate cell populations, including γδ T cells, NK cells, and lymphoid tissue-inducer cells, are early sources of these cytokines during IL-23-driven responses. Epithelial cells and fibroblasts are important cellular targets for IL-17 in vivo; however, recent data suggest that macrophages and B cells are also stimulated directly by IL-17. Thus, Th17 cells interact with multiple populations to facilitate protection against intracellular and extracellular pathogens.

Figure 1.. Extracellular factors controlling Th17 plasticity.

CD4 T cell effector differentiation requires antigen and costimulatory signals derived from APCs. The presence of TGF-β and IL-6 induces IL-21 in T cells, which acts in an autocrine manner through the transcription factor STAT3 to establish Th17 commitment. IL-23 and IL-9 also activate STAT3 to promote Th17 differentiation. The tryptophan photoproduct FICZ induces IL-17 through the Ahr. The transcription factors RORγ and RORα function to stabilize IL-17 expression. Removing TGF-β from the milieu results in Th17 cells converting to Th1, preceded by an intermediate RORγ⁺/α⁺ T-bet⁺ CD161⁺ stage. IL-23 also up-regulates the expression of T-bet and IFN-γ in Th17 cells. Other signals resulting in Th1 conversion include IL-12, IFN-γ, and lymphopenia. In addition, Th17 cells are capable of converting into Tregs and vice versa. For instance, histone deacetylase activity promotes Treg conversion into Th17, suggesting that an epigenetic mechanism contributes to their reciprocal relationship. Further, stimulating Th17 cells with IL-4 increases GATA-binding protein-3 (GATA-3) expression and Th2 conversion. Therefore, effector Th17 cells are highly adaptable to their cytokine microenvironment, which may partially explain their association with pro- and anti-inflammatory functions.

Figure 2.. Th17 effector functions in the lung.

IL-17 and the related cytokine IL-17F stimulate lung epithelial cells through the IL-17RA/IL-17RC complex, inducing mediators that promote granulopoiesis and neutrophil recruitment to the site of infection (G-CSF, SCF, IL-8, MIP-2). In addition, IL-17 facilitates HCO3^– secretion and expression of antimicrobial peptides [i.e., β-defensin-2; (bd-2)], which directly promote bacterial membrane lysis. IL-22 stimulates the IL-22RA/IL-10R2 complex on lung epithelium, facilitating injury repair and antimicrobial gene expression. In addition to these functions, IL-17 directly stimulates macrophages to produce IL-12, enhancing Th1 immunity to intracellular infections. IL-17 promotes humoral immunity by directly stimulating B cells to undergo isotype switching as well as increasing expression of the PIGR on lung epithelium. In this manner, Th17 cells support memory responses to extracellular pathogens.