Human inherited RORγT deficiency encompasses genetic heterogeneity, T cell deficiency, and clinical homogeneity

medRxiv, July 2026

42539146

Iris Fagniez, Miyuki Tsumura, Antoine Guerin, Hassan Abolhassani, Samin Sharafian, Mehrnaz Mesdaghi, Toyoki Nishimura, Harsha Prasada Lashkari, Sadashiva Rao, Stephanie Richards, Ji Eun Han, Ottavia M Delmonte, Camille Kergaravat, Janet G Markle, Masato Ogishi, Jing Han, Jessica Peel, Joseph Vellutini, Yi Feng, Camille Soudée, Mélanie Migaud, Boaz Palterer, Katherine J L Jackson, Shiho Nishimura, Sonoko Sakata, Keishiro Kinoshita, Ayako Yamamoto, Hiroshi Moritake, Mohammed Alzahrani, Francisco Vallejos, Theresa L Cole, Joanne M Smart, Sharon Choo, Zahra Chavoshzadeh, Shahnaz Armin, Antoine Toubert, Peng Zhang, Jeremie Rosain, Luigi D Notarangelo, Qiang Pan-Hammarstrom, Stuart G Tangye, Jean-Laurent Casanova, Cindy S Ma, Anne Puel, Jacinta Bustamante, Satoshi Okada, Stephanie Boisson-Dupuis, Rui Yang

We previously reported inherited RORgammaT 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 TH1* and CD8+ T cells, and impaired Mycobacterium-induced IFN-gamma production by the remaining cells of these subsets, NK cells, conventional CD4+ T, Vdelta1, and Vdelta2 gamma-delta T cells. Most patients also displayed CMC due to their low counts of TH17 and TH1* cells. One patient died from disseminated Bacille Calmette-Guerin (BCG) vaccine infection, but, unexpectedly, all the other patients are still alive and clinically stable. RORgammaT is essential for protective immunity against mycobacteria and Candida in humans.