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- Title
Human IL-23 is essential for IFN-γ–dependent immunity to mycobacteria.
- Authors
Philippot, Quentin; Ogishi, Masato; Bohlen, Jonathan; Puchan, Julia; Arias, Andrés Augusto; Nguyen, Tina; Martin-Fernandez, Marta; Conil, Clement; Rinchai, Darawan; Momenilandi, Mana; Mahdaviani, Seyed Alireza; Keramatipour, Mohammad; Rosain, Jérémie; Yang, Rui; Khan, Taushif; Neehus, Anna-Lena; Materna, Marie; Han, Ji Eun; Peel, Jessica; Mele, Federico
- Abstract
Patients with autosomal recessive (AR) IL-12p40 or IL-12Rβ1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function IL23R variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and Mycobacterium-inducible IFN-γ immunity in both Vδ2+ γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F–dependent immunity to Candida in a single lymphocyte subset but is required for IFN-γ–dependent immunity to Mycobacterium in at least two lymphocyte subsets. IL-23 supports innate IFN-γ production by innate-like T cells: Effective human immunity to mycobacteria depends on IFN-γ made by lymphocytes. IL-12 and IL-23 are related cytokines that contribute to induction of IFN-γ-producing lymphocytes. Philippot et al. screened a large cohort of patients diagnosed with diverse infectious diseases and identified six patients from four families who were homozygous for loss-of-function alleles of the IL-23 receptor (IL-23R) and had a history of mycobacterial disease. In vitro activation studies of blood lymphocytes from these IL-23R-deficient patients and healthy controls revealed a marked defect in IFN-γ production by natural killer cells and two innate-like adaptive T cell subsets in IL-23R-deficient individuals. These new findings reveal that IL-23 is an essential driver of IFN-γ synthesis by multiple innate-like lymphocyte subsets that contribute to host protection from mycobacterial disease.—IRW
- Publication
Science Immunology, 2023, Vol 8, Issue 80, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.abq5204