Figure 3.

Adaptive immune pathways in fibrosis. Naive CD4⁺ T cells differentiate into various distinct functional lineages driven by cues produced by injured epithelial cells and activated antigen presenting cells (dendritic cells and macrophages). Intracellular infections trigger IL-12–driven T_H1 responses that produce IFN-γ, which activates microbicidal and cytotoxic activities that aid in pathogen clearance. Extracellular bacteria and certain fungi can lead to inflammasome activation and IL-6 production and can, in the presence of TGF-β1, drive T_H17 differentiation. IL-17 from T_H17 cells helps recruit neutrophils to clear the infection and exacerbates inflammation. Infection with extracellular, tissue-dwelling helminth parasites drives T_H2 differentiation, with IL-4, IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) from innate and epithelial sources guiding the differentiation of CD4⁺ T_H2 cells. IL-13, when not competed for by the higher-affinity decoy receptor IL-13Rα2, binds its signaling receptor IL-13Rα1, leading to alternative activation of macrophages as well as epithelial apoptosis and myofibroblast activation. T_reg cells are crucial in limiting the magnitude of T_H cell responses and thereby ensure proper regulation of the wound-healing response. There is also a great deal of cross-regulation among T_H cell subsets. For example, IL-13 suppresses T_H17 differentiation, whereas IFN-γ can suppress IL-13–induced fibrosis by inducing classical macrophage activation and suppressing IL-13 and TGF-β1–induced collagen synthesis in myofibroblasts. R_x, pathways being targeted for therapy, either preclinically or in clinical trials; iNOS, inducible nitric oxide synthase; ROS, reactive oxygen species; PMN, polymorphonuclear leukocyte; MUC5AC, mucin-5AC.