biostudies-literatureZhang ZSir Jules Thorn Charitable TrustDeutsche ForschungsgemeinschaftHarvard Medical SchoolNational Institute for Health Research (NIHR)UK National Institute of Health Research Cambridge Biomedical Research CentreNational Institutes of HealthWellcome TrustDivision of Intramural Research, National Institute of Allergy and Infectious Diseases1311-1327https://www.ebi.ac.uk/biostudies/studies/S-EPMC6547869biostudies-literatureUnknown216(6)Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain (<i>IL2RB</i>) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the <i>IL2RB</i> gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recaThe Journal of experimental medicineHuman interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance.PMC6547869101908/Z/13/ZACF-2019-01-004083650/Z/07/Z207556/Z/17/ZGO2955/1-1099966/Z/12/Z12/JTAMcDonald DHaller WRooryck CSinclair JPennamen PAl-Mousa HAcres MAlajlan HJames JRSmith KGCEngelhardt KRGothe FMata CPModis YBrothers SNaudion SDoffinger RNotarangelo LDLenardo MJYamazaki YHambleton SZhang ZAlazami AMZhang YBowen CThaventhiran JEMatthews HFPelluard FfalseHuman interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance.Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain (<i>IL2RB</i>) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the <i>IL2RB</i> gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was reca2019-01-01T00:00:00Z2019 Jun2026-05-04T05:42:17.979Z2025-05-18T13:33:29.954ZS-EPMC65478693104018510.1084/jem.20182304