Research ArticleTUBERCULOSIS

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

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Science Immunology  21 Dec 2018:
Vol. 3, Issue 30, eaau8714
DOI: 10.1126/sciimmunol.aau8714

Faulty kinase purged by Koch’s bacillus

Rare mutations in genes involved in IFN-γ–dependent immunity underpin human genetic susceptibility to severe mycobacterial diseases including primary tuberculosis. Boisson-Dupuis et al. investigated whether two common missense variants of the TYK2 Janus kinase with impaired catalytic activity conferred an increased risk of tuberculosis. Individuals homozygous for the P1104A variant of TYK2 are markedly predisposed to developing primary tuberculosis, defining a common monogenic etiology for the “white plague”. The current frequency of the P1104A allele in European populations is significantly decreased compared to ancient European DNA samples. These findings suggest that negative selection against the TYK2 P1104A allele by endemic tuberculosis in Europe may have contributed to a slow genetic purge of this susceptibility allele during recent millennia.


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.

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