Concordant with the production of pro-inflammatory cytokines such as TNF-α, which activate nonspecific inflammation, innate sensor cells produce additional cytokines that differentially activate specific subsets of ILCs within the first hours of an infection. This is due to the expression of unique MAMPs—or unique combinations of MAMPs—by different types of pathogens, which elicit different patterns of cytokines from innate sensor cells. This has important consequences in directing the type of immune response that will be mounted against the pathogen, as subsets of ILCs are differentially activated to produce their own effector cytokines and chemokines contingent on the pattern of cytokines produced by innate sensor cells (Fig. 11.3). The products of activated ILCs amplify and coordinate local innate responses that are better tailored to resist specific types of pathogens, and also alter the recruitment and maturation of different myelomonocytic innate effector cells (that is, granulocytes like neutrophils, eosinophils, and basophils, or monocytes) at the site of infection. Cytokines produced by ILCs may also guide the development of naive T cells into distinct effector subsets (for example, TH1, TH2, or TH17 cells)—either directly by acting on naive T cells themselves or indirectly by modulating the activation of dendritic cells that migrate to regional lymphoid tissues to prime naive T cells. In this way, ILCs perform an important bridging function during the first few days of an immune response, by both providing for innate defense and influencing the type of adaptive response that follows.
Adaptive immunity is triggered when an infection eludes or overwhelms the innate defense mechanisms and generates a threshold level of antigen (see Fig. 11.1). Adaptive immune responses are then initiated in the local lymphoid
Normal mice and humans Mice and humans lacking innate immunity (PMN– , MAC–) SCID or RAG-defcient mice and humans (PMN+ , MAC+ , T/B–)
Integration of innate and adaptive immunity in response to specific types of pathogens. 449 tissue, in response to antigens presented by dendritic cells activated during the course of the innate immune response (see Fig. 11.2, second and third panels). Antigen-specific effector T cells and antibody-secreting B cells are generated by clonal expansion and differentiation over several days, during which innate responses orchestrated by ILCs ‘buy time’ for the adaptive response to mature. Within several days of infection, antigen-specific T cells and then antibodies are released into the blood, and from there can enter the site of infection (see Fig. 11.2, fourth panel). Adaptive responses are more powerful because antigen-specific targeting of innate effector mechanisms can eliminate pathogens more precisely. For example, antibodies can activate complement to directly kill pathogens; they can opsonize pathogens for enhanced phagocytosis; and they can arm Fc-bearing innate effector cells for release of microbicidal factors or recruit the cytocidal actions of natural killer (NK) cells—these last capabilities known as antibody-dependent cell-mediated cytotoxicity (ADCC). Effector CD8 T cells can directly kill antigen-bearing target cells via similar cytocidal cytotoxic actions, and effector CD4 T cells can directly release cytokines onto macrophages to enhance their microbicidal actions.