Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23

Martı́nez-Barricarte, Rubén; Markle, Janet; Cindy, S.; Deenick, Elissa K.; Ramírez-Alejo, Noé; Mele, Federico; Latorre, Daniela; Mahdaviani, Seyed Alireza; Aytekin, Caner; Mansouri, Davood; Bryant, Vanessa L.; Jabot–Hanin, Fabienne; Deswarte, Caroline; Nieto-Patlán, Alejandro; Surace, Laura; Kerner, Gaspard; Itan, Yuval; Jovic, Sandra; Avery, Danielle T.; Wong, Natalie; Rao, Geetha; Patin, Étienne; Okada, Satoshi; Bigio, Benedetta; Boisson, Bertrand; Rapaport, Franck; Seeleuthner, Yoann; Schmidt, Monika; İkincioğulları, Aydan; Doğu, Figen; Tanır, Gönül; Tabarsi, Payam; Bloursaz, Mohammed Reza; Joseph, Julia K.; Heer, Avneet; Kong, Xiao‐Fei; Migaud, Mélanie; Lazarov, Tomi; Geissmann, Frédéric; Fleckenstein, Bernhard; Arlehamn, Cecilia S. Lindestam; Sette, Alessandro; Puel, Anne; Emile, Jean François; Vosse, Esther van de; Quintana-Murci, Lluı́s; Santo, James P. Di; Abel, Laurent; Boisson–Dupuis, Stéphanie; Bustamante, Jacinta; Tangye, Stuart G.; Sallusto, Federica; Casanova, Jean Laurent

doi:10.1126/sciimmunol.aau6759

Cited by 166 publications

(168 citation statements)

References 71 publications

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“…This observation is consistent with the near-normal counts of Th17 cells in the patients described here, at odds with the data for patients with STAT3 mutations (Milner et al, 2008;Ma et al, 2008Ma et al, , 2015Ma et al, , 2016de Beaucoudrey et al, 2008). Near-normal Th17 cell levels and a lack of CMC were observed in patients with biallelic null mutations of IL6R, IL23R, or IL21R (Kotlarz et al, 2013;Martínez-Barricarte et al, 2018;Spencer et al, 2019;Ma et al, 2016). This suggests that IL-6R, IL-21R, and IL-23R are individually, but not collectively, redundant for Th17 cell differentiation, accounting for CMC in patients with DN STAT3 or AR ZNF341 deficiency, whose cellular responses to IL-6, IL-21, and IL-23 are all impaired.…”

Section: Discussionsupporting

confidence: 90%

“…Some related deficiencies do not have phenotypes overlapping with HIES. Patients with IL-23R deficiency suffer from isolated mycobacteriosis (Martínez-Barricarte et al, 2018), patients with IL-10RA or IL-10RB deficiency suffer from inflammatory bowel disease (Glocker et al, 2011;Kotlarz et al, 2012;Moran et al, 2013), and patients with IFNAR1 or IFNAR2 deficiency suffer from severe viral infections (Duncan et al, 2015;Hernandez et al, 2019). Other deficiencies overlap with HIES.…”

Section: Introductionmentioning

confidence: 99%

“…Collectively, these findings suggest that many, perhaps even most, of the immunological abnormalities seen in patients with STAT3 deficiency, whether biological (high IgE levels), clinical (atopy and recurrent staphylococcal infections), or both (low levels of inflammation), are due to poor cellular responses to IL-6 (Puel and Casanova, 2019), whereas most of the skeletal abnormalities are due to poor responses to IL-11 (craniosynostosis and deciduous tooth retention) or LIF (scoliosis, osteoporosis). The apparent lack of CMC in patients with AR deficiency of IL-6R, IL-10RA, IL-10RB, IL-11R, IL-21R, IL-23R, IFNAR1, IFNAR2, LIF-R, or OSM-R deficiency (Schwerd et al, 2017;Spencer et al, 2019;Nieminen et al, 2011;Mikelonis et al, 2014;Arita et al, 2008;Martínez-Barricarte et al, 2018;Hernandez et al, 2019;Glocker et al, 2011;Kotlarz et al, 2014;Duncan et al, 2015) also suggested that the pathogenesis of impaired IL-17 immunity and CMC in patients with mutations in STAT3 or ZNF341 may involve the disruption of multiple cytokine responsive pathways (Minegishi et al, 2007;Puel et al, 2011;Béziat et al, 2018;Ma et al, 2016). We tested whether new genetic etiologies of AD-HIES could shed light on the pathogenesis of various individual HIES phenotypes.…”

Section: Introductionmentioning

confidence: 99%

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Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Béziat¹,

Sj²,

Chen³

et al. 2020

Journal of Experimental Medicine

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Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Béziat¹,

Sj²,

Chen³

et al. 2020

Journal of Experimental Medicine

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“…In agreement with this, the frequency of peripheral CCR4 + CCR6 + Th17 cells is normal in patients with autosomal recessive IL23R deficiency, but they do not differentiate properly in vitro. A critical step during the differentiation process is the activation of the transcription factor STAT3, which controls the expression of several genes associated with the Th17 program . The importance of STAT3 in this process is demonstrated by patients affected by the hyper‐IgE syndrome, a genetic disease caused by loss of function mutations in the STAT3 locus, that display absence of Th17 cells .…”

Section: Introductionmentioning

confidence: 99%

Biological and clinical significance of T helper 17 cell plasticity

et al. 2019

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Mature T helper (Th) effector cells originate following antigen recognition by naive T precursors. The maturation process is accompanied by the acquisition of specific effector functions that distinguish at least three different T helper subsets: Th1, Th2 and Th17. In general, maturation of somatic cells is accompanied by terminal differentiation. However, accumulating evidence shows that effector T cells retain a certain degree of plasticity. This is especially true for Th17 cells, which have been shown to converge towards other phenotypes in response to specific microenvironmental pressure. In this review we will discuss the experimental evidence that supports the hypothesis of Th17 plasticity, with particular emphasis on the generation of Th17‐derived ‘non‐classic’ Th1 cells, and the molecular networks that control it. Moreover, we will consider why Th17 plasticity is important for host protection, but also why it can have pathogenic functions during chronic inflammation. Regarding the last point, we will discuss a possible role for biological drugs in the control of Th17 plasticity and disease course.

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“…Homozygosity for this allele had previously been shown to strongly protect against a variety of inflammatory conditions (25). The P1104A TYK2 protein can be phosphorylated but remains catalytically inactive, resulting in a selective impairment of the IL-23-dependent induction of IFNγ (24,26). As many as 1/600 Europeans and ∼1/5,000 individuals outside of East Asia and sub-Saharan Africa are homozygous for P1104A (24).…”

mentioning

confidence: 99%

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

Kerner

Ramírez-Alejo

Seeleuthner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common TYK2 P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans and ∼1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96-10.31, P = 2 × 10 −3 ]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with Mycobacterium tuberculosis, as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for TYK2 P1104A may account for ∼1% of TB cases in Europeans.T uberculosis (TB) remains a major global public health problem. About a quarter of the world's population is infected with Mycobacterium tuberculosis (1, 2), resulting in ∼10 million new cases and 1.6 million deaths worldwide in 2017 (3). Nevertheless, only ∼5% of infected individuals develop active TB in their lifetime (1,4). Abundant evidence for the existence of a genetic component of TB in humans has accumulated from classic genetics studies performed from the turn of the 20th century onward, but its molecular architecture has long remained elusive (5-9). From 1996 onward, single-gene inborn errors of IFN-γ immunity have been found to underlie Mendelian susceptibility to mycobacterial disease (MSMD), which is characterized by severe disease caused by poorly virulent mycobacteria (bacillus Calmette-Guérin vaccines and environmental mycobacteria) (10-15). The clinical penetrance for MSMD depends on the genetic etiology and is inversely correlated with the levels of residual IFN-γ immunity (16). From 2001 onward, autosomal recessive interleukin-12 receptor β1 (IL-12Rβ1) and tyrosine kinase 2 (TYK2) deficiencies have also been identified in children with severe TB and without MSMD (17-23). These two deficiencies impair both the IL-12-and IL-23-dependent production of IFN-γ. They are caused by very rare (minor allele frequency, MAF <5 × 10 −5 worldwide) or private loss-of-function alleles.We recently discovered a strong enrichment in homozygosity for the common TYK2 missense variant P1104A in a genetically heterogeneous cohort of patients with TB from countries outside of Europe in which this disease is endemic, relative to ancestryadjusted controls, with an odds ratio (OR) of 89.3 (95% CI, 14.7-1,725, P = 8.37 × 10 −8 ) (24). Homozygosity for P1104A is also a genetic etiology of MSMD, albeit with much lower estimate...

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Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23

Cited by 166 publications

References 71 publications

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Biological and clinical significance of T helper 17 cell plasticity

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

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