Tuberculosis and impaired IL-23–dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant. - Institut Pasteur Access content directly
Journal Articles Science Immunology Year : 2018

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

Zhi Li
Che Kang Lim
  • Function : Author
Dimitry Krementsov
  • Function : Author
Cindy Ma
Durga Sivanesan
  • Function : Author
Rodrigo Naves
  • Function : Author
Patricia Garcia
  • Function : Author
Andrea Guennoun
  • Function : Author
  • PersonId : 975784
Sevgi Pekcan
  • Function : Author
Zafer Caliskaner
  • Function : Author
Jaime Inostroza
  • Function : Author
Beatriz Tavares Costa-Carvalho
  • Function : Author
Antonio de Albuquerque
  • Function : Author
Humberto Garcia-Ortiz
  • Function : Author
Lorena Orozco
  • Function : Author
Tayfun Ozcelik
Ismail Rhorfi
  • Function : Author
Hicham Souhi
  • Function : Author
Hicham Naji Amrani
  • Function : Author
Adil Zegmout
  • Function : Author
Stephen Michnick
  • Function : Author
Ingrid Fleckenstein
  • Function : Author
Nico Marr
Katia Abarca
  • Function : Author
Cory Teuscher
  • Function : Author
Esra Sayar
  • Function : Author
Jamila El-Baghdadi
  • Function : Author
Lennart Hammarström

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.

Dates and versions

pasteur-02070591 , version 1 (18-03-2019)

Identifiers

Cite

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⟩
260 View
0 Download

Altmetric

Share

Gmail Facebook X LinkedIn More