Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23
Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23
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DOI：
10.1126/sciimmunol.aau6759
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发表时间：
2018-12-01
影响因子：
24.8
通讯作者：
Casanova, Jean-Laurent
中科院分区：
文献类型：
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作者：
Martinez-Barricarte, Ruben;Markle, Janet G.;Casanova, Jean-Laurent
在过去的20年里，数百名常染色体隐性遗传、完全IL-12 p40或IL-12 R β 1缺乏症患者被诊断出来。他们通常患有侵袭性分枝杆菌病，偶尔也会患皮肤粘膜念珠菌病。对这些感染的易感性被认为分别是由于IL-12依赖性IFN-γ免疫和IL-23依赖性IL-17 A/IL-17 F免疫的损伤。我们在这里报告的患者常染色体隐性遗传，完全IL-12 R β 2或IL-23 R缺乏，缺乏对IL-12或IL-23的反应，所有的人，出乎意料的是，显示分枝杆菌病没有念珠菌病。我们表明，健康供体的α β T、γ δ T、B、NK、ILC 1和ILC 2细胞优先产生IFN-γ以响应IL-12，而NKT细胞和MAIT细胞优先产生IFN-γ以响应IL-23。我们还发现，产生IFN-γ的CD 4（+）T细胞，特别是分枝杆菌特异性T（H）1* 细胞（CD 45 RA（-）CCR 6（+））的发育依赖于IL-12和IL-23。最后，我们发现IL 12 RB 1、IL 12 RB 2和IL 23 R在一般人群中具有相似的有害变异频率。因此，相对于IL-12 R β 1缺乏症，IL-12 R β 2或IL-23 R缺乏症的症状性患者相对罕见，这是由于临床发病率较低。有症状的IL-23 R-和IL-12 R β 2-缺陷患者比IL-12 R β 1-缺陷患者少，不是因为这些遗传疾病更罕见，而是因为IL-12或IL-23的孤立缺失部分地被用于产生IFN-γ的其他细胞因子补偿，从而提供了一些针对分枝杆菌的保护。这些自然实验表明，人IL-12和IL-23都是对分枝杆菌的最佳IFN-γ依赖性免疫所需的，无论是单独的还是更合作的。
Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12R beta 1 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-12R beta 2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that alpha beta T, gamma delta 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 T(H)1* 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-12R beta 2 or IL-23R deficiency, relative to IL-12R beta 1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12R beta 2-deficient than IL-12R beta 1-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.