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

Abstract

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.

• Authors: Stéphanie Boisson-Dupuis, Noe Ramirez-Alejo, Zhi Li, Etienne Patin, Geetha Rao, Gaspard Kerner, Che Kang Lim, Dimitry N Krementsov, Nicholas Hernandez, Cindy S Ma, Qian Zhang, Janet Markle, Ruben Martinez-Barricarte, Kathryn Payne, Robert Fisch, Caroline Deswarte, Joshua Halpern, Matthieu Bouaziz, Jeanette Mulwa, Durga Sivanesan, Tomi Lazarov, Rodrigo Naves, Patricia Garcia, Yuval Itan, Bertrand Boisson, Alix Checchi, Fabienne Jabot-Hanin, Aurélie Cobat, Andrea Guennoun, Carolyn C Jackson, Sevgi Pekcan, Zafer Caliskaner, Jaime Inostroza, Beatriz Tavares Costa-Carvalho, Jose Antonio Tavares de Albuquerque, Humberto Garcia-Ortiz, Lorena Orozco, Tayfun Ozcelik, Ahmed Abid, Ismail Abderahmani Rhorfi, Hicham Souhi, Hicham Naji Amrani, Adil Zegmout, Frédéric Geissmann, Stephen W Michnick, Ingrid Muller-Fleckenstein, Bernhard Fleckenstein, Anne Puel, Michael J Ciancanelli, Nico Marr, Hassan Abolhassani, María Elvira Balcells, Antonio Condino-Neto, Alexis Strickler, Katia Abarca, Cory Teuscher, Hans D Ochs, Ismail Reisli, Esra H Sayar, Jamila El-Baghdadi, Jacinta Bustamante, Lennart Hammarström, Stuart G Tangye, Sandra Pellegrini, Lluis Quintana-Murci, Laurent Abel, Jean-Laurent Casanova
• Journal: Science immunology (Sci Immunol) Vol. 3 Issue 30 (12 21 2018) ISSN: 2470-9468 [Electronic] United States
• PMID: 30578352 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Interleukin-23
• Interferon-gamma
• TYK2 Kinase
• TYK2 protein, human

Topics

• Cells, Cultured
• Homozygote
• Humans
• Interferon-gamma (immunology)
• Interleukin-23 (deficiency, immunology)
• Mutation, Missense (genetics)
• TYK2 Kinase (genetics, immunology)
• Tuberculosis (immunology)