TH17 cells also produce IL-22, a member of the IL-10 family that acts cooperatively with IL-17 to induce the expression by epithelial cells of antimicrobial proteins (see Fig. 11.16). These include β-defensins and the C-type lectins RegIIIβ and RegIIIγ, all of which can directly kill bacteria (see Section 2-4). IL-22 and IL-17 can also induce epithelial cells to produce metal-binding proteins that are bacteriostatic and fungistatic. Lipocalin-2 limits iron availability to bacterial pathogens; S100A8 and S100A9 are two antimicrobial peptides that heterodimerize to form the antimicrobial protein calprotectin, which sequesters zinc and manganese from microbes. Many of these antimicrobial agents are also produced by neutrophils recruited to the site of infection; calprotectin has been reported to comprise up to a third of the cytosolic protein of neutrophils. IL-22 also stimulates the proliferation and shedding of epithelial cells as a mechanism to deprive bacteria and fungi of a ‘foothold’ for colonization at epithelial surfaces. While ILC3 cells in barrier tissues respond rapidly to pathogens to produce IL-22, pathogen-specific TH17 cells have been shown to amplify and sustain the production of IL-22 at sites of infection.
As in type 1 and type 2 responses, integration of innate and adaptive effector cells in the type 3 response is mediated in large part by the production of pathogen-specific antibodies that opsonize extracellular bacteria and fungi for destruction by neutrophils, macrophages, and complement. TFH cells that develop coordinately with TH17 cells promote the production of high-affinity IgG and IgA antibodies by plasma cells that can express CCR6 and thereby localize to sites of type 3 responses in barrier tissues, where they can arm neutrophils and macrophages ‘on-site.’ Antibodies are the principal immune reactants that clear primary infections by common extracellular bacteria that elicit type 3 responses, such as Staphylococcus aureus and Streptococcus pneumoniae.
11-11 Differentiated effector T cells continue to respond to signals as they carry out their effector functions.
The commitment of CD4 T cells to distinct lineages of effector cells occurs in peripheral lymphoid tissues, such as lymph nodes. However, the effector activities of these cells are not defined simply by the signals received in the lymphoid tissues. Evidence suggests that there is continuous regulation of the expansion and the effector activities of differentiated CD4 cells, in particular those of TH17 and TH1 cells, once they enter sites of infection.