Fig. 9.33 A shared requirement for TGF-β in the differentiation of iTreg and TH17 cells provides a developmental link that reflects their complementary roles in promoting mutualism with the microbiota. a major site for the deployment of iT and Th17 cells is mucosal tissues, particularly the intestines, where the immune system must cope with an extraordinarily high density of microbial organisms that comprise the microbiota. While the microbiota provides its host with important metabolic functions, it also represents a potential threat as some of its constituents are opportunistic pathogens that can cause serious infections if they breach the mucosal barrier. as an adaptation to restrain untoward inflammation directed against the microbiota while retaining the capacity to mount a host-protective immune response should barrier breach occur, the developmental balance between iTreg cells, which suppress inflammatory responses against the microbiota, and Th17 cells, which promote host-protective inflammatory responses, is determined by the balance between production of the vitamin a metabolite all-trans retinoic acid (at-ra) and production of the pro-inflammatory cytokine IL-6 by mucosal dendritic cells. at homeostasis, antigens derived from the microbiota are presented by a specialized subset of resident dendritic cells that produce at-ra, but no IL-6. however, when antigens are recognized in the context of TLr-stimulating signals, at-ra production is suppressed in favor of IL-6, thereby favoring the development of Th17 effector cells.
under homeostatic conditions, TGF-β produced by T cells represses Th1 and Th2 responses in order to promote T development. under inflammatory conditions that favor IL-6 production, TGF-β production by T cells similarly inhibits the activation of Th1 or Th2 responses (upper panels) in order to facilitate the development of Th17 cells, which otherwise would be potently inhibited by IFn-γ or IL-4. Conversely, if signals are present to induce Th1 or Th2 cells, the cytokines IFn-γ or IL-4 produced by them can override the effect of IL-6 and inhibit Th17 development (lower center panel). IFn-γ produced by Th1 cells blocks the growth of Th2 cells (right panels). on the other hand, IL-4 produced by Th2 cells dominantly prevents Th1 cell development in favor of Th2 (left panels). although not shown, all T-cell subsets can produce IL-10 under conditions of chronic antigen stimulation, which inhibits the production of IL-12, IL-4, and IL-23 by dendritic cells and macrophages, thereby suppressing the development and/or maintenance of Th1, Th2, and Th17 cells.
Fig. 9.34 The subsets of CD4 T cells each produce cytokines that can negatively regulate the development or effector activity of other subsets.
IL-4 or IFN-˜can inhibit development of TH17 cells IL-4IFN-˜TH17IL-4IFN-˜IL-4 acts to inhibit differentiation of TH1 cells IFN-˜acts on TH2 cells to inhibit proliferation TH1TH2IL-4TGF-°TGF-°IFN-˜IFN-˜Activated TH2 cells secrete IL-4 Activated TH1 cells secrete IFN-˜TH2TregTH1Treg cells suppress the differentiation and proliferation of TH1 and TH2 cells of pathogen by the innate immune system initiates a chain reaction that links the innate response to the adaptive immune response, which in turn amplifies the innate response. Thus, certain intracellular bacterial infections (for example, mycobacteria and Listeria) induce dendritic cells and macrophages to produce IL-12, favoring the emergence of TH1 effector cells. TH1 cells, in turn, promote enhanced macrophage activation that clears these intracellular pathogens.