Human Inherited RORγT Deficiency: Genetic Heterogeneity, Immunological Impact, and Clinical Homogeneity

We previously reported that inherited human retinoic acid-related orphan receptor gamma T (RORγT) deficiency underlies mycobacterial disease and chronic mucocutaneous candidiasis (CMC) in seven patients from three ancestries (Chilean, Palestinian, and Saudi Arabian). Here, we expand on the molecular, cellular, and clinical consequences of RORγT deficiency in these patients and identify 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, who had received early prophylaxis (11/12), developed mycobacterial disease due to a near-complete depletion of innate-like adaptive T cells, including mucosal-associated invariant T (MAIT) and invariant natural killer T (iNKT) cells, low counts of adaptive TH1* and CD8+ T cells, and impaired mycobacterium-induced IFN-γ production by the remaining cells of these subsets, and by NK cells, conventional CD4+ T, Vδ1, and Vδ2 γδT cells. Most patients (10/12) also displayed CMC due to their low counts of TH17 and TH1* cells. Additional phenotypes included anti-IL-4Rα-responsive eosinophilic disease in one patient and self-resolving skin warts in two patients, probably reflecting TH2-skewing and defective T cell development, respectively. Finally, one patient (1/12) died from disseminated Bacille Calmette-Guérin (BCG) infection, whereas all the other patients remain alive and clinically stable at ages of 2 to 20 years. Thus, inherited human RORγT deficiency underlies mycobacterial disease with complete penetrance and CMC, with high but incomplete penetrance.