Human IFN-gamma immunity to mycobacteria is governed by both IL-12 and IL-23
Journal Title
Science Immunology
Publication Type
Journal Article
Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rbeta1 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-gamma immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rbeta2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that alphabeta T, gammadelta T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-gamma in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-gamma in response to IL-23. We also show that the development of IFN-gamma-producing CD4(+) T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RA(-)CCR6(+)), 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-12Rbeta2 or IL-23R deficiency, relative to IL-12Rbeta1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12Rbeta2-deficient than IL-12Rbeta1-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-gamma, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-gamma-dependent immunity to mycobacteria, both individually and much more so cooperatively.
WEHI Research Division(s)
PubMed ID
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Creation Date: 2019-02-05 08:28:50
Last Modified: 2019-02-05 08:47:21
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