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

Rubén Martínez-Barricarte, Janet G. Markle, Cindy S. Ma, Elissa K. Deenick, Noé Ramírez-Alejo, Federico Mele, Daniela Latorre, Seyed Alireza Mahdaviani, Caner Aytekin, Davood Mansouri, Vanessa L. Bryant, Fabienne Jabot-Hanin, Caroline Deswarte, Alejandro Nieto-Patlán, Laura Surace, Gaspard Kerner, Yuval Itan, Sandra Jovic, Danielle T. Avery, Natalie WongGeetha Rao, Etienne Patin, Satoshi Okada, Benedetta Bigio, Bertrand Boisson, Franck Rapaport, Yoann Seeleuthner, Monika Schmidt, Aydan Ikinciogullari, Figen Dogu, Gonul Tanir, Payam Tabarsi, Mohammed Reza Bloursaz, Julia K. Joseph, Avneet Heer, Xiao Fei Kong, Mélanie Migaud, Tomi Lazarov, Frédéric Geissmann, Bernhard Fleckenstein, Cecilia Lindestam Arlehamn, Alessandro Sette, Anne Puel, Jean François Emile, Esther van de Vosse, Lluis Quintana-Murci, James P. Di Santo, Laurent Abel, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Stuart G. Tangye, Federica Sallusto, Jean Laurent Casanova

Research output: Contribution to journalArticlepeer-review

129 Scopus citations


Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12R1 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- immunity and IL-23–dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12R2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that T, T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN- in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN- in response to IL-23. We also show that the development of IFN-–producing CD4+ T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RACCR6+), 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-12R2 or IL-23R deficiency, relative to IL-12R1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R– and IL-12R2–deficient than IL-12R1–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-, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-–dependent immunity to mycobacteria, both individually and much more so cooperatively.

Original languageEnglish (US)
Article numbereaau6759
JournalScience Immunology
Issue number30
StatePublished - 2018
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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