Human-inherited RORγT deficiency encompasses genetic heterogeneity, T cell deficiency, and clinical homogeneity
We previously reported inherited retinoic acid-related orphan receptor γ T (RORγT) deficiency in seven patients from three ancestries (Chilean, Palestinian, and Saudi Arabian) with mycobacterial disease and chronic mucocutaneous candidiasis (CMC). We report here five additional patients from different ancestries (Afghan, Indian, Iranian, Japanese, and 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 mucosa-associated invariant T and invariant natural killer T cells, low counts of adaptive TH1* 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 TH17 and TH1* cells. One patient died from disseminated Bacille Calmette-Guérin vaccine infection, but, unexpectedly, all the other patients are still alive and clinically stable at ages of 2 to 20 years. RORγT is essential for protective immunity against mycobacteria and Candida in humans.
Authors
- Antoine Toubert (ORCID: https://orcid.org/0000-0002-7308-7317)
- Toyoki Nishimura (ORCID: https://orcid.org/0000-0002-4196-4880)
- Jing Han (ORCID: https://orcid.org/0000-0003-2307-438X)
- Francisco Vallejos
- Satoshi Okada (ORCID: https://orcid.org/0000-0002-4622-5657)
- Mehrnaz Mesdaghi (ORCID: https://orcid.org/0000-0001-7951-0967)
- Shiho Nishimura
- Ji Eun Han (ORCID: https://orcid.org/0000-0003-1112-9320)
- Shahnaz Arman
- Hassan Abolhassani (ORCID: https://orcid.org/0000-0002-4838-0407)
- S. Cindy (ORCID: https://orcid.org/0000-0001-5387-8413)
- Jérémie Rosain (ORCID: https://orcid.org/0000-0002-2822-161X)
- Mélanie Migaud (ORCID: https://orcid.org/0000-0003-3062-1214)
- Qiang Pan‐Hammarström (ORCID: https://orcid.org/0000-0003-1990-8804)
- Samin Sharafian (ORCID: https://orcid.org/0000-0002-2037-0274)
- Janet Markle.
- Katherine Jackson (ORCID: https://orcid.org/0000-0002-9952-7069)
- Camille Kergaravat (ORCID: https://orcid.org/0009-0003-7301-9343)
- Stuart G. Tangye (ORCID: https://orcid.org/0000-0002-5360-5180)
- Sonoko Sakata (ORCID: https://orcid.org/0000-0002-3775-9673)
- Keishiro Kinoshita (ORCID: https://orcid.org/0009-0007-6898-6602)
- Masato Ogishi (ORCID: https://orcid.org/0000-0003-2421-7389)
- Zahra Chavoshzadeh (ORCID: https://orcid.org/0000-0003-1869-8630)
- Miyuki Tsumura (ORCID: https://orcid.org/0000-0002-8272-9588)
- Boaz Palterer (ORCID: https://orcid.org/0000-0003-2499-8250)
- Rui Yang (ORCID: https://orcid.org/0000-0003-4427-2158)
- Iris Fagniez (ORCID: https://orcid.org/0009-0009-9900-3001)
- Theresa Cole
- Sadashiva Rao
- Sharon Choo
- Harsha Prasada
- Stéphanie Boisson-Dupuis
- Ayako Yamamoto
- Joseph Vellutini
- Luigi D. Notarangelo
- Antoine Guerin
- Ottavia M. Delmonte
- Jacinta Bustamante
- Yi Feng
- Jessica Peel
- Joanne Smart
- Mohammed Alzahrani
- Anne Puel
- Jean-Laurent Casanova
- Peng Zhang
- Hiroshi Moritake
- Camille Soudee
- Stephanie Richards
Institutions
- Hiroshima University (JP)
- University of Miyazaki (JP)
- The University of Sydney (AU)
- Royal Children's Hospital (AU)
- Howard Hughes Medical Institute (US)
- Kyushu University (JP)
- Garvan Institute of Medical Research (AU)
- Inserm (FR)
- Manipal Academy of Higher Education (IN)
- Baylor College of Medicine (US)
- Université Paris Cité (FR)
- Karolinska Institutet (SE)
- UNSW Sydney (AU)
- Hospital for Sick Children Pediatric Center (US)
- Sorbonne Paris Cité (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Research Institute for Endocrine Sciences (IR)
- Children's Medical Center (IR)
- Security Forces Hospital (SA)
- National Institute of Allergy and Infectious Diseases (US)
- Institut Cochin (FR)
- Hospital Dr. Gustavo Fricke (CL)
- Pediatrics and Genetics (US)
- Texas Children's Hospital (US)
- Institut des Maladies Génétiques Imagine (FR)
- Shahid Beheshti University of Medical Sciences (IR)
- Rockefeller University (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2026-09-04
- DOI
- https://doi.org/10.1084/jem.20252038
- Primary Topic
- Immunodeficiency and Autoimmune Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Howard Hughes Medical Institute
- King Baudouin Foundation United States
- St. Giles Foundation
- Immune Deficiency Foundation
- Stony Wold-Herbert Fund
- Japan Agency for Medical Research and Development
- Rockefeller University
- Fondation du Souffle
- SCOR Corporate Foundation for Science
- Japan Society for the Promotion of Science London
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ministry of Education, Culture, Sports, Science and Technology
- Fondation pour la Recherche Médicale
- Agence Nationale de Recherches sur le Sida et les Hépatites Virales
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Honjo International Scholarship Foundation
- Université Sorbonne Paris Cité
- National Institutes of Health
- National Health and Medical Research Council
- National Institute of Allergy and Infectious Diseases
- National Center for Advancing Translational Sciences