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Here we identify human interleukin-2 receptor (IL-2R) \u03b2 chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB 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-2R\u03b2 and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2R\u03b2 expression and function. IL-2R\u03b2 loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2R\u03b2 also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2\u2013based therapeutics for immunological diseases and cancer.<\/jats:p>","DOI":"10.1084\/jem.20182304","type":"journal-article","created":{"date-parts":[[2019,4,30]],"date-time":"2019-04-30T14:47:39Z","timestamp":1556635659000},"page":"1311-1327","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":86,"title":["Human interleukin-2 receptor \u03b2 mutations associated with defects in immunity and peripheral tolerance"],"prefix":"10.1084","volume":"216","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3831-2272","authenticated-orcid":true,"given":"Zinan","family":"Zhang","sequence":"first","affiliation":[{"name":"Cambridge Institute of Therapeutic Immunology and Infectious Disease, and the Department of Medicine, University of Cambridge, Cambridge, UK 1"},{"name":"Molecular Development of the Immune System Section, Laboratory of Immune System Biology and Clinical 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