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

Journal article

Publication Details

Author(s): Martinez-Barricarte R, Markle JG, Ma CS, Deenick EK, Ramirez-Alejo N, Mele F, Latorre D, Mandaviani SA, Aytekin C, Mansouri D, Bryant VL, Jabot-Hanin F, Deswarte C, Nieto-Patlan A, Surace L, Kerner G, Itan Y, Jovic S, Avery DT, Wong N, Rao G, Patin E, Okada S, Bigio B, Boisson B, Rapaport F, Seeleuthner Y, Schmidt M, Ikinciogullari A, Dogu F, Tanir G, Tabarsi P, Bloursaz MR, Josephs JK, Heer A, Kong XF, Migaud M, Lazarov T, Geissmann F, Fleckenstein B, Arlehamn CL, Sette A, Puel A, Emile JF, Van De Vosse E, Quintana-Murci L, Di Santo JP, Abel L, Boisson-Dupuis S, Bustamante J, Tangye SG, Sallusto F, Casanova JL
Journal: Science immunology
Publication year: 2018
Volume: 3
Journal issue: 30
ISSN: 2470-9468


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.

FAU Authors / FAU Editors

Fleckenstein, Bernhard Prof. Dr.
Medizinische Fakultät

External institutions with authors

Ankara University / Ankara Üniversitesi
Dr. Sami Ulus Children's Hospital / Dr. Sami Ulus Kadın Doğum, Çocuk Sağlığı ve Hastalıkları Eğitim ve Araştırma Hastanesi
Hiroshima University
Hôpital Necker-Enfants malades
Institut Pasteur
La Jolla Institute for Immunology
Leiden University
Memorial Sloan Kettering Cancer Center
Rockefeller University
Shahid Beheshti University of Medical Sciences
Università della Svizzera italiana (USI)
University of New South Wales (UNSW)
Versailles Saint-Quentin-en-Yvelines University / Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
Walter and Eliza Hall Institute of Medical Research (WEHI)

How to cite

Martinez-Barricarte, R., Markle, J.G., Ma, C.S., Deenick, E.K., Ramirez-Alejo, N., Mele, F.,... Casanova, J.-L. (2018). Human IFN-gamma immunity to mycobacteria is governed by both IL-12 and IL-23. Science immunology, 3(30).

Martinez-Barricarte, Ruben, et al. "Human IFN-gamma immunity to mycobacteria is governed by both IL-12 and IL-23." Science immunology 3.30 (2018).


Last updated on 2019-07-02 at 09:23