Human IL-23 is essential for IFN-γ–dependent immunity to mycobacteria

Philippot, Quentin; Ogishi, Masato; Bohlen, Jonathan; Puchan, Julia; Arias, Andrés Augusto; Nguyen, Tina; Martín-Fernández, Marta; Conil, Clement; Rinchai, Darawan; Momenilandi, Mana; Mahdaviani, Seyed Alireza; Keramatipour, Mohammad; Rosain, Jérémie; Yang, Rui; Khan, Taushif; Neehus, Anna-Lena; Materna, Marie; Han, Ji Eun; Peel, Jessica N.; Mele, Federico; Weißhaar, Marc; Jovic, Sandra; Bastard, Paul; Lévy, Romain; Voyer, Tom Le; Zhang, Peng; Renkilaraj, Majistor Raj Luxman Maglorius; Arango-Franco, Carlos Andrés; Pelham, Simon J.; Seeleuthner, Yoann; Pochon, Mathieu; Ata, Manar; Alali, Fatima; Migaud, Mélanie; Soudée, Camille; Kochetkov, Tatiana; Molitor, Anne; Carapito, Raphaël; Bahram, Seiamak; Boisson, Bertrand; Fieschi, Claire; Mansouri, Davood; Marr, Nico; Okada, Satoshi; Shahrooei, Mohammad; Parvaneh, Nima; Chavoshzadeh, Zahra; Cobat, Aurélie; Patel, Roosheel S.; Abel, Laurent; Tangye, Stuart G.; Cindy, S.; Béziat, Vivien; Sallusto, Federica; Boisson–Dupuis, Stéphanie; Bustamante, Jacinta; Casanova, Jean‐Laurent; Puel, Anne

doi:10.1126/sciimmunol.abq5204

Cited by 31 publications

(24 citation statements)

References 95 publications

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“…Memory B cells, polyclonal serum Ig levels, and/or Ag‐specific Abs induced following infection or routine vaccination are unaffected by IEI that disrupt signaling via IL‐12/IL‐12R ( IL12B , IL12RB1 , IL12RB2) , IL‐23/IL‐23R ( IL12B, IL12RB1 , IL23R ), IFNα/IFNαR ( IFNAR1 , IFNAR2 ), or IFNγ/IFNγR ( IFNG , IFNGR1 , IFNGR2 ) 168,169,177,178,181–184,194 . These observations were also made for individuals with pathogenic biallelic variants in TBX21 , encoding Tbet that is induced by IL‐12 and IFNγ signaling, or RORC encoding RORγt induced by IL‐23 195–197 .…”

Section: Mechanisms Underpinning Cellular Defects and Clinical Featur...mentioning

confidence: 89%

“…or IFNγ/IFNγR (IFNG, IFNGR1, IFNGR2). 168,169,177,178,[181][182][183][184]194 These observations were also made for individuals with pathogenic biallelic variants in TBX21, encoding Tbet that is induced by IL-12 and IFNγ signaling, or RORC encoding RORγt induced by IL-23. [195][196][197] Consistent with this, memory B-cell formation and serum Ig levels are within or exceed normal ranges in patients with LOF mutations in STAT1, which is also activated by several of these cytokines.…”

Section: Iei Identify Redundant and Non-redundant Roles For Cytokines...mentioning

confidence: 95%

“…43,78,122,153,171,172 Thus, when we first discovered a memory B-cell deficit in STAT3 DN HIES patients in 2010, 99 it was difficult to ascribe a non-redundant requirement for a specific STAT3-activating cytokine (or cytokines) in human memory B-cell formation and, by extension, humoral immunity. However, subsequent discoveries of individuals with germline variants in IL21R, 141,[173][174][175] IL21, 176 IL6R, 131,132 IL6ST, 129,130,137,138 IL12RB2, 177 IL23R, 177,178 IL2RB, 179,180 IFNAR1/IFNAR2, [181][182][183] IFNG, 184 and earlier findings of IEI due to mutations in IL2RG, 42 IL2RA, [185][186][187] IL7/IL7R, [188][189][190] IL10/IL10R, 191,192 IFNG/IFNGR1/IFNGR2, 193 or IL12B/ IL12RB1, 194 provided mechanistic insights into the requirements of these individual cytokines in human B-cell responses. or IFNγ/IFNγR (IFNG, IFNGR1, IFNGR2).…”

Section: Iei Identify Redundant and Non-redundant Roles For Cytokines...mentioning

confidence: 99%

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The trajectory of human B‐cell function, immune deficiency, and allergy revealed by inborn errors of immunity

Tangye,

Mackie,

Pathmanandavel

et al. 2023

Immunological Reviews

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SummaryThe essential role of B cells is to produce protective immunoglobulins (Ig) that recognize, neutralize, and clear invading pathogens. This results from the integration of signals provided by pathogens or vaccines and the stimulatory microenvironment within sites of immune activation, such as secondary lymphoid tissues, that drive mature B cells to differentiate into memory B cells and antibody (Ab)‐secreting plasma cells. In this context, B cells undergo several molecular events including Ig class switching and somatic hypermutation that results in the production of high‐affinity Ag‐specific Abs of different classes, enabling effective pathogen neutralization and long‐lived humoral immunity. However, perturbations to these key signaling pathways underpin immune dyscrasias including immune deficiency and autoimmunity or allergy. Inborn errors of immunity that disrupt critical immune pathways have identified non‐redundant requirements for eliciting and maintaining humoral immune memory but concomitantly prevent immune dysregulation. Here, we will discuss our studies on human B cells, and how our investigation of cytokine signaling in B cells have identified fundamental requirements for memory B‐cell formation, Ab production as well as regulating Ig class switching in the context of protective versus allergic immune responses.

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Section: Mechanisms Underpinning Cellular Defects and Clinical Featur...mentioning

confidence: 89%

Section: Iei Identify Redundant and Non-redundant Roles For Cytokines...mentioning

confidence: 95%

Section: Iei Identify Redundant and Non-redundant Roles For Cytokines...mentioning

confidence: 99%

See 1 more Smart Citation

The trajectory of human B‐cell function, immune deficiency, and allergy revealed by inborn errors of immunity

Tangye,

Mackie,

Pathmanandavel

et al. 2023

Immunological Reviews

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“…These results complement those of a recent study where the systemic effects of IL-23 inhibition were examined by phenotyping individuals with IL23R deficiency. Interestingly, the analysis of this rare condition uncovered prominent defects of IFN-γ responses and only a limited impairment of IL-17 activity ( 26 ). Thus, the consequences of IL-23 inhibition may be organ specific.…”

Section: Discussionmentioning

confidence: 99%

Single-cell analysis of psoriasis resolution reveals an inflammatory fibroblast state targeted by IL-23 blockade

Francis,

McCluskey,

Ganier

et al. 2023

Preprint

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Biologic drugs targeting the IL-23/IL-17 axis have transformed outcomes for people living with psoriasis, allowing most patients to achieve skin clearance. Despite the potential to reveal fundamental regulators of skin homeostasis, the early mechanisms of action of these drugs remain poorly understood. Here, we performed longitudinal single-cell RNA sequencing in individuals with psoriasis who had been successfully treated with IL-23 inhibitor therapy. By profiling skin at baseline, day 3 and day 14 of treatment, we demonstrated that IL-23 blockade causes marked gene expression shifts, with fibroblast and myeloid populations displaying the most extensive changes at day 3. We identified a transientWNT5A+/IL24+fibroblast state, which was only detectable in lesional skin. The study of ligand-receptor interactions revealed that pro-inflammatory signals stemming from theseWNT5A+/IL24+fibroblasts upregulated multiple genes in differentiated keratinocytes. Importantly, the abundance ofWNT5A+/IL24+fibroblasts was significantly reduced after treatment. This observation was validatedin-silico, by deconvolution of multiple transcriptomic datasets, and experimentally, by RNAin situhybridization of additional skin samples. These findings demonstrate that the evolution of inflammatory fibroblast states is a key feature of resolving psoriasis skin.

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“…Very recent data have demon-strated the important role of IL-23 signaling in infectious conditions. Patients with autosomal recessive IL-23R deficiency display Mendelian susceptibility to mycobacterial disease due to impaired IFN-γ production and, less frequently, to chronic mucocutaneous candidiasis due to impaired IL-17A/F production [11]. Here, we focus on two questions: what are the immune cells that express the IL23R and how is IL23R expression acquired.…”

Section: Introductionmentioning

confidence: 99%