Tuberculosis and impaired IL-23–dependent IFN- immunity in humans homozygous for a common TYK2 missense variant
Inherited IL-12R1 and TYK2 deficiencies impair both IL-12– and IL-23–dependent IFN- 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-, IL-10, or even IL-12, which, like IL-23, induces IFN- 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- by IL-23 and is a common monogenic etiology of tuberculosis.
|Authors||Stephanie Boisson-Dupuis1,2,3*+, Noe Ramirez-Alejo1+, Zhi Li4,5++, Etienne Patin6,7,8++, Geetha Rao9++, Gaspard Kerner2,3++, Che Kang Lim10,11++, Dimitry N. Krementsov12++, Nicholas Hernandez1, Cindy S. Ma9,13, Qian Zhang14, Janet Markle1, Ruben Martinez-Barricarte1, Kathryn Payne9, Robert Fisch1, Caroline Deswarte2,3, Joshua Halpern1, Matthieu Bouaziz2,3, Jeanette Mulwa1, Durga Sivanesan15,16, Tomi Lazarov17, Rodrigo Naves18, Patricia Garcia19, Yuval Itan1,20,21, Bertrand Boisson1,2,3, Alix Checchi2,3, Fabienne Jabot-Hanin2,3, Aurelie Cobat2,3, Andrea Guennoun14, Carolyn C. Jackson1,22, Sevgi Pekcan23, Zafer Caliskaner24, Jaime Inostroza25, Beatriz Tavares Costa-Carvalho26, Jose Antonio Tavares Albuquerque27, Humberto Garcia-Ortiz28, Lorena Orozco28, Tayfun Ozcelik29, Ahmed Abid30, Ismail Abderahmani Rhorfi31, Hicham Souhi30, Hicham Naji Amrani30, Adil Zegmout30, Frederic Geissmann17, Stephen W. Michnick15, Ingrid Muller-Fleckenstein31, Bernhard Fleckenstein31, Anne Puel1,2,3, Michael J. Ciancanelli1, Nico Marr32, Hassan Abolhassani10,33, Maria Elvira Balcells34, Antonio Condino-Neto27, Alexis Strickler35, Katia Abarca36, Cory Teuscher37, Hans D. Ochs38, Ismail Reisli39, Esra H. Sayar39, Jamila El-Baghdadi40, Jacinta Bustamante1,2,3,41SS, Lennart Hammarstrom10,11,42SS, Stuart G. Tangye9,13SS, Sandra Pellegrini4,5SS, Lluis Quintana-Murci6,7,8SS, Laurent Abel1,2,3||, Jean-Laurent Casanova|
|Responsible Garvan Author|
|Publisher Name||Science Immunology|
|Published Pages||pii: eaau8714|