Human-inherited RORγT deficiency encompasses genetic heterogeneity, T cell deficiency, and clinical homogeneity
Abstract
Abstract We previously reported inherited RORγT deficiency in seven patients from three ancestries (Chilean, Palestinian, Saudi Arabian) with mycobacterial disease and chronic mucocutaneous candidiasis (CMC). We report here five additional patients from different ancestries (Afghan, Indian, Iranian, Japanese, Sri Lankan), each homozygous for a new loss-of-function RORC variant. All but one patient — the exception receiving early prophylaxis — developed mycobacterial disease due to a near-complete depletion of innate-like adaptive T cells, including MAIT and iNKT cells, low counts of adaptive T H 1* and CD8 + T cells, and impaired Mycobacterium -induced IFN-γ production by the remaining cells of these subsets, NK cells, conventional CD4 + T, Vδ1, and Vδ2 γδT cells. Most patients also displayed CMC due to their low counts of T H 17 and T H 1* cells. One patient died from disseminated Bacille Calmette-Guérin (BCG) vaccine infection, but, unexpectedly, all the other patients are still alive and clinically stable. RORγT is essential for protective immunity against mycobacteria and Candida in humans.
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Authors: Iris Fagniez, Miyuki Tsumura, Antoine Guerin, Hassan Abolhassani, Samin Sharafian, Mehrnaz Mesdaghi, Toyoki Nishimura, Harsha Prasada, Sadashiva Rao, Stephanie Richards, Ji Eun Han, Ottavia M. Delmonte, Camille Kergaravat, Janet Markle., Masato Ogishi, Jing Han, Jessica Peel, Joseph Vellutini, Yi Feng, Camille Soudee, Mélanie Migaud, Boaz Palterer, Katherine Jackson, Shiho Nishimura, Sonoko Sakata, Keishiro Kinoshita, Ayako Yamamoto, Hiroshi Moritake, Mohammed Alzahrani, Francisco Vallejos, Theresa Cole, Joanne Smart, Sharon Choo, Zahra Chavoshzadeh, Shahnaz Arman, Antoine Toubert, Peng Zhang, Jérémie Rosain, Luigi D. Notarangelo, Qiang Pan‐Hammarström, Stuart G. Tangye, Jean-Laurent Casanova, S. Cindy, Anne Puel, Jacinta Bustamante, Satoshi Okada, Stéphanie Boisson-Dupuis, Rui Yang
Institutions: Karolinska Institutet, The University of Sydney, UNSW Sydney, Inserm, Kyushu University, Université Paris Cité, Sorbonne Paris Cité, Assistance Publique – Hôpitaux de Paris, Royal Children's Hospital, Manipal Academy of Higher Education, Rockefeller University, Shahid Beheshti University of Medical Sciences, Research Institute for Endocrine Sciences, Baylor College of Medicine, Garvan Institute of Medical Research, Howard Hughes Medical Institute, Hiroshima University, Vanderbilt University Medical Center, Texas Children's Hospital, National Institute of Allergy and Infectious Diseases, Institut Cochin, University of Miyazaki, Children's Medical Center, Institut des Maladies Génétiques Imagine, Security Forces Hospital, Pediatrics and Genetics, Hospital Dr. Gustavo Fricke, Hospital for Sick Children Pediatric Center