Kavli Affiliate: Jean-Laurent Casanova
| Authors: Diana Olguin Calderon, Laura E. Kilpatrick, Clement Conil, Quentin Philippot, Masato Ogishi, Joseph Vellutini, Ji Eun Han, Narelle Keating, Hailun Li, Geetha Rao, Jonathan Bohlen, Charles S. Lay, Simon Platt, Gaspard Kerner, Elsa Feredj, Jessica Peel, Mana Momenilandi, Yoann Seeleuthner, Candice Laine, camille soudee, Claire Leloup, Cecile Debuisson, Fanny Lanternier, Samuel Bitoun Bitoun, Stephan Pavy, Xavier Mariette, Aniss Rafik, Hanaa Skhoun, Hanane EL Ouazzani, Ismail Abderahmani-Ghorfi, Jamila EL Baghdadi, Andres Baena, Manuela Tejada-Giraldo, Luis Fernando Barrera, Andres Augusto Arias, Giovanna Fabio, Maria Carrabba, Melike Emiroglu, Liliana Bezrodnik, Loubna EL Zein, Hassan Hammoud, Peter Gregersen, Benjamin Terrier, Rafael Leon Lopez, Marion Touzet, Vincent Pestre, Marlene Pasque t, Lars Rogge, Michael Fayon, Francois Galode, Eric Jeziorski, Darragh Duffy, Lluis Quintana-Murci, Etienne Patin, Charlotte Cunningham-Rundles, Isabelle Meyts, Shen-Ying Zhang, Qian Zhang, Emmanuelle Jouanguy, Bertrand Boisson, Jeremie Rosain, Vivien Beziat, Mohammad Shahrooei, Seyed Alireza Mahdaviani, Nima Rezaei, Nima Parvaneh, Zahra Chavoshzadeh, Niloufar Yazdanpanah, Nathalie Aladjidi, Antoni Noguera-Julian, Ana Esteve-Sole, Laia Alsina, Davood Mansouri, Sevgi Keles, Mediha Gonenc ortakoylu, Deniz Aygun Aygun, Esra Yucel, Ayca Kiykim, Yildiz Camcioglu, Cindy Ma, Stuart Tangye, Peng Zhang, Laurent Abel, Peter D. Craggs, Jean-Laurent Casanova, Aurelie Cobat, Anne Puel, Jacinta Bustamante, Stephen J Hill and Stephanie Boisson-Dupuis
| Summary:
Homozygosity for rare loss-of-function IL23R variants abolishes IL-23-dependent IFN-γ production by lymphocytes, including NK and innate-like T cells, thereby underlying clinical disease due to weakly virulent mycobacterial species. We report selective enrichment in homozygosity for four hypomorphic IL23R variants in our cohort of patients with tuberculosis. Three of these IL23R alleles are rare (G300V, G149R and L372F), with a minor allele frequency (MAF) under 1%, but the fourth (R381Q) is surprisingly common, with a MAF as high as 10.2% in certain populations. The other 15 missense alleles found in the homozygous state in public databases are isomorphic. The four hypomorphic IL-23R variants identified dimerize with IL-12Rβ1 and bind IL-23. However, their function is impaired by low levels of cell-surface expression (R381Q, G300V) and/or as a consequence of conformational changes altering agonist efficacy. IFN-γ production in response to IL-23 is impaired in innate-like T cells and NK cells. These data suggest that recessive partial IL-23R deficiency, whether due to rare or common variants, confers a predisposition to tuberculosis while preserving immunity to less virulent mycobacteria.
One sentence summary Homozygous hypomorphic IL23R variants impair IL-23-dependent IFN-γ production and underlie tuberculosis.