Autosomal recessive T-bet and RORgammaT deficiencies underlie mycobacterial susceptibility

Abstract

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by selective, inherited predisposition to clinical disease caused by weakly virulent mycobacteria, such as M.bovis BCG vaccines and environmental mycobacteria (EM). Twenty MSMD-causing genes have been identified. Their mutations affect IFN-γ-related immune circuits by impairing either the production of, the cellular response to IFN-γ, or both. T-bet and RORγT are transcription factors that govern the lineage commitment of two different T helper lineages, TH1 and TH17 cells, respectively, in mice. Surprisingly, both autosomal recessive (AR) T-bet and RORγT deficiencies in humans underlie mycobacterial susceptibility. Here we summarize the molecular, cellular, and clinical features of a recently identified patient with AR T-bet deficiency and three new patients with AR RORγT deficiency. Human AR T-bet deficiency underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γST cells) as well as IFN-γ produced by them. It also underlies peripheral eosinophilia and recurrent upper respiratory inflammation due to excessive production of TH2 cytokines, particularly IL-5 and IL-13, by CD4+ αβT cells. Although humoral immunity in inherited T-bet deficiency remains grossly intact, T-bet is required for the in vivo and in vitro development of a distinct subset of human B cells in humans resembling murine “age-associated B cells” that are associated with infection and autoimmunity. We also identified three new patients with AR RORγT deficiency that underlies both mycobacterial and fungal susceptibility. Inherited RORyT deficiency abolishes the development of iNKT and MAIT cells, two IFN-γ-producing innate-like adaptive T cell subsets, and impairs the production of IFN-γ by Vδ2+ γδT cells in response to mycobacterial stimulation. The production of IFN-γ by purely adaptive apT cells remains largely intact upon mycobacterium-specific stimulation. The development of TH17 cells and the production of TH17 cytokines are abolished in inherited RORyT deficiency, thereby underlying susceptibility to C.albicans. Collectively, impaired development of and defective production of IFN-γ by MAIT, V82+ γ8T cells, and iNKT cells are sufficient to cause mycobacterial susceptibility, whereas the contribution of purely adaptive apT cells to antimycobacterial immunity, at least against M.bovis BCG or EM, is probably inconsequential.Table 1(abstract: 257) ML-model Scores for IEI Test Cohort Baseline vs. Enhanced Model/Manual vs. Automated Term Extractioncase_dxscore_bn36_manualscore_bn47_update_manualscore_change_expertPrediction_Expert_BN36score_bn36_automaticscore_bn47_update_automaticscore_bn_change_HPOPrediction_HPO_BN36CVID0.991.000.0111.001.000.001SIgAD0.060.880.8210.140.690.551AT0.891.000.1110.020.110.090Hypogam0.541.000.4610.040.960.920Hypogam1.001.000.0011.001.000.001AT0.101.000.9011.001.000.001THIG0.020.690.6700.170.840.671CVID vs. Hypogam0.030.900.8701.001.000.001DGS0.541.000.4610.330.930.601DGS0.451.000.5510.380.990.611CVID-common variable immunodeficiency, SIgAD-selective IgA deficiency, AT-ataxia telangiectasia, Hypogam-hypogammaglobulinemia, THIG-transient hypogammaglobulinemia of infancy, DGS-Digeorge SyndromeTable 2(abstract: 257) Full feature set and frequency comparision by term extraction method.ConceptManualAutomated HPOBarnard Exact p_valueimm_dx_test0.70.30.06care_team0.60naMeds0.50naFatigue0.40.60.26iei_dz_mention0.40.4nasn_jiearing_loss0.30naAbscess0.20.10.34iei_gene_mention0.20naclin_care0.20naexam_findings0.20.7***0.021lymphoma0.20.2Napna_fewer_two0.20.40.26pna_greater_two0.20.11thrombocytopenia0.20.2naopportunistic infection0.20.2nahypocalcemia0.20.11Ataxia0.20narec_fever0.20naother_infect0.20.50.11FTT0.10.6***0.011Otorrhea0.10nalymphadenopathy0.10.40.076dysmorphic_feat0.10.1naWarts0.10naSepsis0.10nasinusitis_greater_four0.10nafe_def0.10.20.34lymphopenia0.10.30.16neutropenia0.10.20.34mycobact_dz0.10namycosis_superficial0.10nainv_herpes_dz0.10nagranuloma_skin0.10naaspergillosis0.10naChemo0.10nametabolics0.10.1napolyarthritis0.00naorganomegaly0.00.3naseptic_shock0.00nahyper-eos0.00.1nameningococcal_dz0.00naSle0.00.1nabronchiectasis0.00.1napulm_fibrosis0.00naAiha0.00naencephalitis0.00naheme_manifestation0.00.4na***denotes significant difference at a type I error rate of 0.05 [Display omitted]