期刊
SCIENCE IMMUNOLOGY
卷 3, 期 30, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.aau6759
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资金
- National Institute of Allergy and Infectious Diseases (NIAID) [5R37AI095983, R01AI089970, K99AI127932]
- National Center for Research Resources
- National Center for Advancing Sciences (NCATS) of the NIH [UL1TR001866]
- Rockefeller University
- St. Giles Foundation
- European Research Council [323183, ERC-2010-AdG-268777]
- Institut National de la Sante et de la Recherche Medicale (INSERM), Paris Descartes University
- Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]
- French National Research Agency (ANR) [ANR-10-IAHU-01]
- ANR-TBPATHGEN [ANR-14-CE14-0007-01]
- ANR-IFNPHOX [ANR13-ISV3-0001-01]
- ANR-GENMSMD [ANR16-CE17-0005-01]
- NIAID [U19AI118626, 1K99AI127932-01A1]
- Canadian Institutes of Health Research
- NIH Translational Science Award (CTSA) program [UL1 TR000043]
- Swiss National Science Foundation [IZKOZ3_173586]
- Charles H. Revson Foundation
- European Molecular Biology Organization (EMBO)
- National Council of Science and Technology of Mexico (CONACYT) [264011]
- Stony Wold-Herbert Fund Fellowship Grant
- AXA Research Fund
- National Health and Medical Research Council of Australia
- Office for Health and Medical Research of the State Government of NSW Australia
- NIH [HHSN272200900044C]
- SRC2017
- Helmut Horten Foundation
- Japanese Society for the Promotion of Science [16H05355]
- Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development
- European Research Council (ERC) [323183] Funding Source: European Research Council (ERC)
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.
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