Impaired IL-23–dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency

Abstract

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23–dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

“…This analysis also confirms our previous findings of an enrichment in rare pLOF variants of 13 genes involved in TLR3-and IRF7-dependent type I IFN immunity to seasonal influenza virus in critical cases relative to controls with mild/asymptomatic infection [14]. These results were strengthened by the addition of TYK2, which was recently shown to underlie severe COVID-19 [18,19], and TLR7, especially under a recessive model. We found that homozygous/hemizygous carriers of rare pLOF or bLOF variants at the 15 loci had a significantly higher risk of life-threatening COVID-19 than heterozygotes.…”

“…Through a candidate approach focusing on influenza susceptibility genes, the COVID Human Genetics Effort (CHGE, www.covidhge.com) provided proof-of-concept that autosomal inborn errors of TLR3-dependent and -independent type I interferon (IFN) immunity, including autosomal recessive (AR) deficiencies of IFNAR1 or IRF7, can underlie critical COVID-19 [14]. Other children with AR IFNAR1, IFNAR2, TBK1, or STAT2 deficiency were subsequently reported, as well as children with AR TYK2 deficiency [15][16][17][18][19] (Figure 1). Some other groups were unable to replicate these findings, but the variants were not tested biochemically and it is unclear whether recessive defects were considered [11,[20][21][22].…”

Genome-wide detection of human variants that disrupt intronic branchpoints

“…We identified 14 individuals’ RNA-seq data that we previously published in different studies ( 30 , 48 , 57 – 59 ), whose paired WES data were also available in-house ( SI Appendix , Table S9 ). We used BPHunter for genome-wide detection, retained SNVs and deletions that had BPHunter scores ≥3, removed variants that failed quality checking, and obtained 69 variants to be validated.…”

Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis

“…By challenging ITK-deficient leukocytes (obtained long after the clinical remission of TB) with BCG, we demonstrated profoundly impaired IL-23-dependent IFN-γ production by MAIT and Vδ2 + γδ T lymphocytes, two well-established IFN-γ–producing lymphocyte subsets ( Le Bourhis et al, 2010 ; Chen, 2016 ), and partially impaired IFN-γ production by CD4 + , CD8 + , and DN αβ T lymphocytes. Indeed, the impairment of IL-23 signaling confers a predisposition to TB in humans ( Boisson-Dupuis et al, 2018 ; Ogishi et al, 2022 ). Overall, inherited ITK deficiency functionally impedes multiple IFN-γ–producing lymphocyte subsets, leading to insufficient protection against TB, but sufficient immunity to BCG and environmental mycobacteria.…”

“…Patients with these disorders are also prone to TB, which may even be the only clinical phenotype for genotypes displaying incomplete penetrance for MSMD. Multiple patients with autosomal recessive (AR) complete TYK2 and IL-12Rβ1 deficiencies have been diagnosed with TB ( Altare et al, 2001 ; Kreins et al, 2015 ; Boisson-Dupuis and Bustamante, 2021 ; Ogishi et al, 2022 ). Moreover, homozygosity for TYK2 P1104A, which selectively impairs IL-23–dependent IFN-γ production, is a common and highly penetrant genetic etiology of TB, but a rare and weakly penetrant etiology of MSMD ( Boisson-Dupuis et al, 2018 ; Kerner et al, 2019 , 2021 ; Casanova and Abel, 2022 ).…”