Tuberculosis and impaired IL-23–dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant.

Stéphanie Boisson-Dupuis (1, 2) , Noe Ramirez-Alejo (1) , Zhi Li (3) , Etienne Patin (4, 5) , Geetha Rao (6) , Gaspard Kerner (2) , Che Kang Lim , Dimitry Krementsov , Nicholas Hernandez (1) , Cindy Ma (6) , Qian Zhang (7, 1) , Janet Markle (1) , Ruben Martinez-Barricarte (1) , Kathryn Payne (6) , Robert Fisch (1) , Caroline Deswarte (2) , Joshua Halpern (1) , Matthieu Bouaziz (2) , Jeanette Mulwa (1) , Durga Sivanesan , Tomi Lazarov (8) , Rodrigo Naves , Patricia Garcia , Yuval Itan (1) , Bertrand Boisson (1, 2) , Alix Checchi (2) , Fabienne Jabot-Hanin (2) , Aurélie Cobat (2) , Andrea Guennoun (9) , Carolyn Jackson (1) , Sevgi Pekcan , Zafer Caliskaner , Jaime Inostroza , Beatriz Tavares Costa-Carvalho , Antonio de Albuquerque , Humberto Garcia-Ortiz , Lorena Orozco , Tayfun Ozcelik , Ahmed Abid (10) , Ismail Rhorfi , Hicham Souhi , Hicham Naji Amrani , Adil Zegmout , Frederic Geissmann (8) , Stephen Michnick , Ingrid Fleckenstein , Bernhard Fleckenstein (11) , Anne Puel (1, 2) , Michael Ciancanelli (1) , Nico Marr (12) , Hassan Abolhassani (13) , María Elvira Balcells (14) , Antonio Condino-Neto (15) , Alexis Strickler (16) , Katia Abarca , Cory Teuscher , Hans Ochs (17) , Ismail Reisli (18) , Esra Sayar , Jamila El-Baghdadi , Jacinta Bustamante (1, 2, 19) , Lennart Hammarström , Stuart G. Tangye (20) , Sandra Pellegrini (3) , Lluis Quintana-Murci (5, 4) , Laurent Abel (21, 2) , Jean-Laurent Casanova (21, 2, 22)

1 St. Giles Laboratory of Human Genetics of Infectious Diseases
2 Equipe Inserm U1163 - Human genetics of infectious diseases : Mendelian predisposition
3 Signalisation des Cytokines - Cytokine Signaling
4 C3BI - Centre de Bioinformatique, Biostatistique et Biologie Intégrative
5 Génétique Evolutive Humaine - Human Evolutionary Genetics
6 Garvan Institute of medical research
7 MoBS - Laboratory for the Modeling of Biological and Socio-technical Systems [Boston]
8 Memorial Sloane Kettering Cancer Center [New York]
9 Laboratory of Genetic Medicine & Immunology
10 BDTLN - Bases de données et traitement des langues naturelles
11 Institute of Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
12 Sidra Medicine [Doha, Qatar]
13 TUMS - Tehran University of Medical Sciences
14 Infectious Diseases Department, School of Medicine
15 Institute of Biomedical Sciences - Department of Immunology [Sao Paulo]
16 Hosp Puerto Montt
17 University of Washington [Seattle]
18 Selcuk University
19 CHU Necker - Enfants Malades [AP-HP]
20 Garvan Institute for Medical Research
21 Inserm U980 - Génétique Humaine des Maladies Infectieuses
22 Service d'immuno-hématologie pédiatrique [CHU Necker]

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls (P = 8.37 × 10-8; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.

Domains: Life Sciences [q-bio]; Immunology; Life Sciences [q-bio]; Genetics

Stéphanie Boisson-Dupuis, Noe Ramirez-Alejo, Zhi Li, Etienne Patin, Geetha Rao, et al.. Tuberculosis and impaired IL-23–dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant.. Science Immunology, 2018, 3 (30), pp.eaau8714. ⟨10.1126/sciimmunol.aau8714⟩. ⟨pasteur-02070591⟩