The Role of T Helper ()17 Cells as a Double-Edged Sword in the Interplay of Infection and Autoimmunity with a Focus on Xenobiotic-Induced Immunomodulation
Figure 2
Differentiation and commitment of IL-17-producing T helper (TH)17 cells in the midpoint of other coacting cells in favor of and against the harboring individual. Upon antigen recognition, presentation and cosignaling, naïve (TH0) cells differentiate in the presence of distinct cytokine milieu into effecter (TH1, TH2, TH9, TH17, TH22, and TFH) and T regulatory (TReg) cells. Signaling cytokine and other molecules activate lineage-unique transcription factors that ultimately mediate cell differentiation and maturation. Whereas activation of STAT1 induces T-bet expression, STAT6 signaling upregulates GATA3 expression; both cell lineages reciprocally regulate each other and regulate the generation of TH17 cells through their hallmark effecter cytokines, IFN- and IL-4, respectively, though IFN- is produced by TH17 cells in some disease settings and in response to certain infections. Differentiation of TH17 necessitates costimulatory signals of CD28 and ICOS (the last is not mandatory) and the absence of TH1 and TH2 cytokines (IL-12/IFN- and IL-4) and their master transcription factors; a task taken over by TGF- is to constrain TH1 and TH2 during TH17 differentiation program. TH17 and TReg are likely descendants of the same ancestor cell lineage, which differentiates in presence of low levels of TGF- and IL-6/IL-21 or other proinflammatory cytokines (IL-1, TNF-, and IL-18) into TH17 cells; TGF- signals through Smad2 protein pathway and is indispensable for induction of expression RORt. High levels of TGF- alone induce Foxp3 expression and hence TReg cell differentiation. Following their final commitment and upregulation of IL-23R, TH17 cells require IL-23 signaling that is crucial for their survival and effecter functions including production of IL-22, as well as, cell plasticity including later production of IFN-. TH22 may differentiate from TH0 cells or through a local commitment of TH17 cells homed in the epidermis. Contributions of TH17 cells entail activations of aryl hydrocarbon receptor (AhR) signaling and production of IL-22 upon exposure to xenobiotic substances. IL-17 and IL-17F increase production of IL-6, IL-8, prostaglandin E2 (PGE2), monocyte chemotactic protein-(MCP-) 1, and the granulocyte colony-stimulating factor (G-CSF) by various cells including macrophages, fibroblasts, keratinocytes, and epithelial and endothelial cells and ultimately promote inflammatory diseases, AD, and/or cancer. These cytokines together with IL-21 and IL-22 are also implicated in mediating protective as well as pathogenic processes in various disease settings.
