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Interleukin-12 and the regulation of innate resistance and adaptive immunity

Key Points

  • Interleukin-12 (IL-12) is a heterodimeric pro-inflammatory cytokine that regulates T-cell and natural killer-cell responses, induces the production of interferon-γ (IFN-γ), favours the differentiation of T helper 1 (TH1) cells and is an important link between innate resistance and adaptive immunity.

  • Although phagocytes were reported originally to be the main cell types that produce IL-12, subsets of dendritic cells (DCs) are the first producers of IL-12 in response to pathogens during infections.

  • The differential production of IL-12 by DC subsets in response to various pathogens is dependent on differences in the regulation of expression of the gene encoding IL-12, patterns of Toll-like receptor (TLR) expression, and cross-regulation between the different subsets, involving cytokines such as IL-10 and type I IFN.

  • Maturation of CD4+ and CD8+ T cells into type-1 cytokine-producing cells is differentially regulated, indicating the different relative roles of IL-12 and other factors in favouring maturation of the two cell types.

  • Recently, it has become evident, however, that TH1 responses might take place in the absence of IL-12 and that IL-12 might be only one of the members of a family of heterodimeric cytokines, also including IL-23 and IL-27, that are involved in the regulation of TH1 responses.

Abstract

Interleukin-12 (IL-12) is a heterodimeric pro-inflammatory cytokine that induces the production of interferon-γ (IFN-γ), favours the differentiation of T helper 1 (TH1) cells and forms a link between innate resistance and adaptive immunity. Dendritic cells (DCs) and phagocytes produce IL-12 in response to pathogens during infection. Production of IL-12 is dependent on differential mechanisms of regulation of expression of the genes encoding IL-12, patterns of Toll-like receptor (TLR) expression and cross-regulation between the different DC subsets, involving cytokines such as IL-10 and type I IFN. Recent data, however, argue against an absolute requirement for IL-12 for TH1 responses. Our understanding of the relative roles of IL-12 and other factors in TH1-type maturation of both CD4+ and CD8+ T cells is discussed here, including the participation in this process of IL-23 and IL-27, two recently discovered members of the new family of heterodimeric cytokines.

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Figure 1: Summary of the biology of IL-12.
Figure 2: Structure and putative evolution of IL-12 and its receptor.
Figure 3: IL-12 receptor and signal transduction.
Figure 4: Model of TH1-cell differentiation.

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Acknowledgements

I thank R. Kastelein, X.-J. Ma and K. Murphy for discussions and for sharing of unpublished data.

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DATABASES

LocusLink

IFN-γ

IL-4

IL-12

IL-12Rβ1

IL-12Rβ2

IL-23

IL-27

p35

p40

TLRs

Glossary

INTERFERONS

(IFNs). Proteins with potent antiviral activity that are of particular importance during the early response to pathogens. Type I or viral IFNs comprise families (α, β and ω) of homologous proteins that interact with a common two-chain receptor (composed of IFNAR1 and IFNAR2), and type II or immune IFN is represented by a single protein (IFN-γ) that interacts with a different two-chain receptor (composed of IFN-γR1 and IFN-γR2).

TOLL-LIKE RECEPTORS

(TLRs). Receptors present on mammalian cells, mostly on cells that are involved in innate or adaptive resistance to pathogens, that are homologous to the Toll-receptor gene family in Drosophila, members of which have important roles in both embryogenesis and defence against infection. TLRs have evolved to recognize pathogen-associated molecular patterns (PAMPs) that are conserved between and shared by many microbial pathogens.

T HELPER 1/2

(TH1/TH2). Functional subsets of CD4+ T cells expressing T-cell receptor-αβ that produce either type-1 cytokines (IL-2, IFN-γ and other cytokines that support macrophage activation, the generation of cytotoxic T cells and the production of opsonizing antibodies) or type-2 cytokines (IL-4, IL-5, IL-13 and other cytokines that support B-cell activation, the production of non-opsonizing antibodies, allergic reactions and the expulsion of extracellular parasites).

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Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3, 133–146 (2003). https://doi.org/10.1038/nri1001

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