Other Cytokines Produced During Innate Immune Responses

In addition to TNF, IL-1, and IL-6, dendritic cells and macrophages activated by PAMPs and DAMPs produce other cytokines that have important roles in innate immune responses (see Table 4-4). Some of the main features of these cytokines and their roles in innate immunity are discussed in this section. These cytokines also have important effects in stimulating adaptive immunity, as we will discuss later in this chapter and in more detail in Chapters 9 and 10.

IL-12 is secreted by dendritic cells and macrophages and stimulates IFN-y production by NK cells and T cells enhances NK cell and CTL-mediated cytotoxicity, and promotes differentiation of Th1 cells. IL-12 exists as a disulfide-linked heterodimer of 35-kD (p35) and 40-kD (p40) subunits. The p35 subunit is a member of the type I cytokine family. In addition to IL-12, there are other heterodimeric cytokines whose subunits are homologous to either or both of the IL-12 p35 and p40 chains, including IL-23, IL-27, and IL-35. This is of significance because therapeutic antibodies specific for shared subunits are in development for treatment of inflammatory diseases, and some of these antibodies may block the function of more than one cytokine. The principal sources of IL-12 are activated dendritic cells and macrophages. Many cells appear to synthesize the p35 subunit, but macrophages and dendritic cells are the main cell types that produce the p40 component and therefore the biologically active cytokine. During innate immune reactions to microbes, IL-12 is produced in response to TLR and other pattern recognition receptor signaling induced by many micro-bial stimuli, including bacterial LPS or lipoteichoic acid and virus infections. IFN-y produced by NK cells or T cells also stimulates IL-12 production, contributing to a positive feedback loop.

The receptor for IL-12 (IL-12R) is a heterodimer composed of P1 and P2 subunits, both of which are members of the type I cytokine receptor family. Both chains are required for high-affinity binding of IL-12 and for signaling, which activates the transcription factor STAT4. Expression of the P2 chain of the IL-12 receptor is itself enhanced by IFN-y, whose production is stimulated by IL-12, and this is another example of a positive amplification loop in immune responses. Studies with gene knockout mice and the phenotype of rare patients with mutations in the IL-12 receptor support the conclusion that IL-12 is important for IFN-y production by NK cells and T cells and for host resistance to intracellular bacteria and some viruses. For example, patients with mutations in the IL-12 receptor P1 subunit have been described, and they are highly susceptible to infections with intracellular bacteria, notably Salmonella and atypical mycobacteria. IL-12 secreted by DCs during antigen presentation to naive CD4+ T cells promotes their differentiation into the TH1 subset of helper T cells, which are important for defense against intracellular infections (see Chapter 9). This is a key way in which innate immunity shapes adaptive immune responses.

IL-18 enhances the functions of NK cells, similar to IL-12. Recall that the production of IL-18, like that of IL-1, is dependent on the inflammasome. Also like IL-1, IL-18 binds to a receptor that signals through a TIR domain.

IL-15 is cytokine that serves important growth-stimulating and survival functions for both NK cells and T cells. IL-15 is structurally homologous to the T cell growth factor IL-2, and the heterotrimeric IL-15 receptor shares two subunits with the IL-2 receptor. An interesting feature of IL-15 is that it can be expressed on the cell surface bound to the a chain of its receptor and in this form can be presented to and stimulate nearby cells that express a receptor composed of the other two chains (P and y). IL-15 presented this way by dendritic cells to NK cells in lymph nodes activates signaling pathways that promote NK cell IFN-y production. IL-15 also serves as a survival factor for NK and memory CD8+ T cells.

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