A novel immunoregulatory function for IL‐23: Inhibition of IL‐12‐dependent IFN‐γ production

Abstract

Most studies investigating the function of IL-23 have concluded that it promotes IL-17-secreting T cells. Although some reports have also characterized IL-23 as having redundant pro-inflammatory effects with IL-12, we have instead found that IL-23 antagonizes IL-12-induced secretion of IFN-c. When splenocytes or purified populations of T cells were cultured with IL-23, IFN-c secretion in response to IL-12 was dramatically reduced. The impact of IL-23 was most prominent in CD8 1 T cells, but was also observed in NK and CD81 T cells in IL-23p19-deficient mice as compared with WT mice. This increase in IFN-c production coincided with increased LM clearance at days 2 and 3 post-infection. Our data suggest that IL-23 may be a key factor in determining the responsiveness of lymphocytes to IL-12 and their subsequent secretion of IFN-c.Key words: CD8 1 T cells . Cytokines . Innate immunity . Listeria monocytogenes Introduction IL-23 is an IL-12 family cytokine which is composed of the IL-12p40 subunit and a novel cytokine subunit, p19. The heterodimeric structure of IL-23 binds to a receptor complex containing the IL-12Rb1 and a novel receptor termed IL-23R [1]. Similar to IL-12, IL-23 is secreted by activated macrophages and dendritic cells [2] in response to gram-positive and -negative bacterial, viral, and fungal infections, as well as multiple other stimuli [3][4][5][6][7][8][9][10][11]. The majority of the research investigating the actions of IL-23 has focused on its role in maintaining populations of IL-17-secreting cells as well as the possibility of directly inducing IL-17 and IL-22 secretion from a variety of cell types (for reviews see [2,12]). Initially, however, IL-23 was found to have some overlapping functions with IL-12. In a previous report, stimulation of human CD4 1 T cells with anti-CD3 and anti-CD28 resulted in IFN-g secretion, which could be significantly enhanced by IL-12 and slightly enhanced by . Contrary to this, using the murine system, several studies have suggested that IL-23 does not induce production of IFN-g in CD4 1 T cells [13,14]. In this article, we also provide evidence that murine CD4 1 and CD8 1T cells do not respond to IL-23 by secreting IFN-g. IL-23 has been shown to play a role in infectious diseases, autoimmunity and cancer. Mice deficient in IL-23 show increased susceptibility to Mycobacterium tuberculosis, Klebsiella pneumoniae, Citrobacter rodentium, Toxoplasma gondii, Salmonella enterica, and Cryptococcus neoformans [15][16][17][18][19][20][21][22][23]. Increased susceptibility to these infections was linked to the ability of IL-23 to regulate the production of IL-17 and IL-22, although during certain infections, IL-23 does not regulate both cytokines. Figure 1. IL-12, but not IL-23, induces the differentiation of IFN-g secreting T cells. Purified CD8 1 (A, B, D, and E) or CD4 1 (C and F) T cells from naïve WT B6 mice were cultured 6 days on plates coated with anti-CD3 and soluble anti-CD28 in IL-2-supplemented medium with 5 ng/mL IL-12, 10 ng/ mL IL-23, or no additional ...

IL-23 in Infections, Inflammation, Autoimmunity and Cancer: Possible Role in HIV-1 and AIDS

“…IL-23 → IFN γ: The reverse situation was observed in regulation of IFNγ production by IL-23 in murine lymphocytes (Sieve et al 2010). IL-23 antagonizes IL-12-induced secretion of IFNγ.…”

IL‐23R Deficiency Does Not Impact Atherosclerotic Plaque Development in Mice

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IL-23 Gene Expression in PBMCs of Patients with Coronary Artery Disease

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