Interleukin-12 (IL-12) is a heterodimeric pro-inflammatory cytokine that induces the production of interferon-gamma (IFN-gamma), favours the differentiation of T helper 1 (T(H)1) 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 T(H)1 responses. Our understanding of the relative roles of IL-12 and other factors in T(H)1-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.

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

After encountering antigen, helper T (T(H)) cells undergo differentiation to effector cells, which can secrete high levels of interferon-gamma, interleukin-4 (IL-4), IL-10 and other immunomodulators. How T(H) cells acquire, and remember, new patterns of gene expression is an area of intensive investigation. The process is remarkably plastic, with cytokines being key regulators. Extrinsic signals seem to be integrated into cell-intrinsic programming, in what is becoming an intriguing story of regulated development. We summarize the latest insights into mechanisms that govern the lineage choices that are made during T(H)-cell responses to foreign pathogens.

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The lineage decisions of helper T cells

Interferon-gamma (IFN-gamma) is crucial for immunity against intracellular pathogens and for tumor control. However, aberrant IFN-gamma expression has been associated with a number of autoinflammatory and autoimmune diseases. This cytokine is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by Th1 CD4 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops. Herein, we briefly review the functions of IFN-gamma, the cells that produce it, the cell extrinsic signals that induce its production and influence the differentiation of naive T cells into IFN-gamma-producing effector T cells, and the signaling pathways and transcription factors that facilitate, induce, or repress production of this cytokine. We then review and discuss recent insights regarding the molecular regulation of IFN-gamma, focusing on work that has led to the identification and characterization of distal regulatory elements and epigenetic modifications with the IFN-gamma locus (Ifng) that govern its expression. The epigenetic modifications and three-dimensional structure of the Ifng locus in naive CD4 T cells, and the modifications they undergo as these cells differentiate into effector T cells, suggest a model whereby the chromatin architecture of Ifng is poised to facilitate either rapid opening or silencing during Th1 or Th2 differentiation, respectively.

Regulation of interferon-gamma during innate and adaptive immune responses.

The T helper lymphocyte is responsible for orchestrating the appropriate immune response to a wide variety of pathogens. The recognition of the polarized T helper cell subsets Th1 and Th2 has led to an understanding of the role of these cells in coordinating a variety of immune responses, both in responses to pathogens and in autoimmune and allergic disease. Here, we discuss the mechanisms that control lineage commitment to the Th1 phenotype. What has recently emerged is a rich understanding of the cytokines, receptors, signal transduction pathways, and transcription factors involved in Th1 differentiation. Although the picture is still incomplete, the basic pathways leading to Th1 differentiation can now be understood in in vitro and a number of infection and disease models.

Molecular Mechanisms RegulatinG Th1 Immune Responses

To examine the function of IL-10 synthesis during early infection with the intracellular protozoan Toxoplasma gondii, IL-10 knockout (KO) mice were inoculated with an avirulent parasite strain (ME-49). In contrast to control littermates that displayed 100% survival, the IL-10-deficient animals succumbed within the first 2 wk of the infection, with no evidence of enhanced parasite proliferation. The mortality in the IL-10 KO mice was associated with enhanced liver pathology characterized by increased cellular infiltration and intense necrosis. Levels of IL-12 and IFN-gamma in sera of infected IL-10-deficient animals were four- to sixfold higher than those in sera from control mice, as were mRNA levels for IFN-gamma, IL-1 beta, TNF-alpha, and IL-12 in lung tissue. Similarly, macrophages from IL-10 KO mice activated in vitro or in vivo with T. gondii produced higher levels of TNF-alpha and IL-12 than macrophages from control animals. Moreover, spleen cells from IL-10 KO mice infected with T. gondii secreted more IFN-gamma than splenocytes from nondeficient animals. In vitro depletion experiments indicated that CD4+ lymphocytes are the major source of the latter cytokine in the spleen cell populations, and in vivo depletion with anti-CD4 Abs protected the IL-10 KO mice from parasite-induced mortality. Together the data suggest that endogenous IL-10 synthesis plays an important role in vivo in down-regulating monokine and IFN-gamma responses to acute intracellular infection, thereby preventing host immunopathology.

In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal

IL-12 is required for the development of IFN-γ-dependent resistance to intracellular pathogens but is not thought to play a major role in its maintenance. To directly assess the requirement for continuous IL-12 signaling in long-term cell-mediated immunity, recombinant cytokine was transiently administered to IL-12 p40-deficient mice during the first 2 wk of infection with the intracellular pathogen Toxoplasma gondii. As expected, these animals survived the acute phase and established chronic infections. However, 4–6 wk after IL-12 withdrawal, the mice exhibited increased brain cyst burdens and succumbed to toxoplasmic encephalitis. Reactivation was associated with a loss of T-dependent IFN-γ production without a concomitant increase in Th2 cytokine expression. Importantly, parasite Ag-induced IFN-γ synthesis by purified T cells from these animals could be restored by in vitro exposure to IL-12. These results argue that endogenous IL-12 is required for the long-term maintenance of IFN-γ-dependent resistance against intracellular pathogens.

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Cutting Edge: IL-12 Is Required for the Maintenance of IFN-γ Production in T Cells Mediating Chronic Resistance to the Intracellular Pathogen, Toxoplasma gondii

Michael Pesin

Papers

Cutting Edge: IL-12 Is Required for the Maintenance of IFN-γ Production in T Cells Mediating Chronic Resistance to the Intracellular Pathogen, Toxoplasma gondii