TH17 cells are stimulated to release IL-17A and IL-17F when they encounter antigen at sites of infection (Fig. 11.16). A primary effect of these cytokines is the enhanced production and recruitment of neutrophils. The receptor for
TH17 IL-17 and IL-22 produced by TH17 cells induce the production of antimicrobial peptides by epithelial cells IL-17 IL-22 antimicrobial peptides IL-22 produced by TH17 increases epithelial cell turnover Increased epithelial cell division and shedding impairs bacterial colonization Direct killing or growth inhibition of bacteria attached to the epithelium turnover IL-22
Fig. 11.16 The immune response to extracellular bacteria produce cytokines that activate local epithelial and stromal cells to and some fungi is coordinated by activated TH17 cells. TH17 coordinate the immune response to extracellular bacteria and some cells activated by antigen-bearing macrophages and dendritic cells types of fungi. in barrier tissues (e.g., intestinal or respiratory mucosa, and skin)
IL-17 produced by TH17 cells activates stromal cells and myeloid cells to produce G-CSF, which stimulates neutrophil production in bone marrow IL-17IL-17 G-CSF stromal cell myeloid cell bone marrow neutrophil production
Increases numbers of circulating neutrophils to sustain supply of short-lived innate effectors at infection site
Fig. 11.17 The cytokines IL-12 and IL-23 have a component in common, as do their receptors. The heterodimeric cytokines IL-12 and IL-23 both contain the p40 subunit, and the receptors for IL-12 and IL-23 have the IL-12Rβ1 subunit in common, which binds the p40 subunit. IL-12 signaling primarily activates the transcriptional activator STAT4, which increases IFN-γ production. IL-23 primarily activates STAT3, but also activates STAT4 weakly (not shown). Both cytokines augment the activity and proliferation of the CD4 subsets that express receptors for them; TH1 cells express IL-12R, and TH17 cells express primarily IL-23R, but can also express low levels of IL-12R (not shown). Mice deficient in p40 lack expression of both of these cytokines, and manifest immune defects as a result of deficiencies in both TH1 and TH17 activities.
IL-17A and IL-17F is expressed widely on cells such as fibroblasts, epithelial cells, and keratinocytes. IL-17 induces these cells to secrete various cytokines, including IL-6, which amplifies the TH17 response, and the hematopoietic factor granulocyte colony-stimulating factor (G-CSF), which increases the production of neutrophils by the bone marrow. IL-17 also stimulates production of the chemokines CXCL8 and CXCL2, the receptors for which (CXCR1 and CXCR2) are uniquely expressed by neutrophils (see Fig. 11.8). Thus, one important action of IL-17 at sites of infection is to induce local cells to secrete cytokines and chemokines that attract neutrophils.