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

Ruben Martinez-Barricarte 1 Janet Markle * Cindy Ma 2 Elissa Deenick 2 Noe Ramirez-Alejo Federico Mele 3 Daniela Latorre 3 Alireza Mahdaviani 4 Caner Aytekin 5 Davood Mansouri 4 Vanessa Bryant 6, 7, 8 Fabienne Jabot-Hanin 9 Caroline Deswarte 10, 9 Alejandro Nieto-Patlán 9 Laura Surace 11 Gaspard Kerner 9, 10 Yuval Itan 12 Sandra Jovic 3 Danielle Avery 2 Natalie Wong 2 Geetha Rao 2 Etienne Patin 13, 14, 15 Satoshi Okada 16 Benedetta Bigio 1 Bertrand Boisson 10, 9 Franck Rapaport Yoann Seeleuthner 10, 9 Monika Schmidt 17 Aydan Ikinciogullari 18 Figen Dogu 18 Gonul Tanir 5 Payam Tabarsi 4 Mohammed Reza Bloursaz 4 Julia Joseph 1 Avneet Heer 1 Xiao-Fei Kong 1 Mélanie Migaud 10, 9 Tomi Lazarov 19 Frédéric Geissmann 19, 20, 21 Bernhard Fleckenstein 17 Cecilia Arlehamn 22 Alessandro Sette 22, 23 Anne Puel 1, 10, 9 Jean-François Emile 24 Esther van de Vosse 25 Lluis Quintana-Murci 13, 14, 15 James Santo 1 Laurent Abel 10, 9 Stephanie Boisson-Dupuis 10, 9 Jacinta Bustamante 9, 10 Stuart Tangye 2 Federica Sallusto 3, 26 Jean-Laurent Casanova 10, 9, 27, *
* Corresponding author
Abstract : 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 (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-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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Ruben Martinez-Barricarte, Janet Markle, Cindy Ma, Elissa Deenick, Noe Ramirez-Alejo, et al.. Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23. Science Immunology, American Association for the Advancement of Science, 2018, 3 (30), pp.eaau6759. ⟨10.1126/sciimmunol.aau6759⟩. ⟨hal-02352927⟩

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