Research ArticleCYTOKINES

Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23

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Science Immunology  21 Dec 2018:
Vol. 3, Issue 30, eaau6759
DOI: 10.1126/sciimmunol.aau6759

Cytokines team up to fend off mycobacteria

IFN-γ is the linchpin cytokine needed for the human immune system to successfully defend against mycobacterial infection. Martínez-Barricarte et al. investigated IFN-γ production and T cell differentiation in patients with rare immunodeficiencies resulting from mutations in the genes encoding the subunits of the IL-12 and IL-23 receptors. Individuals lacking only the IL-12Rβ2 or IL-23R subunits had fewer T cell abnormalities and less mycobacterial disease than individuals with a defect in the IL-12Rβ1 chain shared between the IL-12 and IL-23 receptors. Achieving a full IFN-γ response by all lymphocyte subsets requires cooperation between IL-12 and IL-23; some subsets respond preferentially to IL-12, whereas others are more sensitive to IL-23. These results demonstrate the partial redundancy of IL-12 and IL-23 in supporting IFN-γ–mediated protection against mycobacterial infections.


Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rβ1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12–dependent IFN-γ immunity and IL-23–dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rβ2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αβ T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ–producing CD4+ T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RACCR6+), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rβ2 or IL-23R deficiency, relative to IL-12Rβ1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R– and IL-12Rβ2–deficient than IL-12Rβ1–deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ–dependent immunity to mycobacteria, both individually and much more so cooperatively.

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