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susceptibility to mycobacterial disease (MSMD) due to autosomal recessive, complete T-bet deficiency, which impairs IFN-\u03b3 production by innate and innate-like adaptive, but not mycobacterial-reactive purely adaptive, lymphocytes. Here, we explore the persistent upper airway inflammation (UAI) and blood eosinophilia of this patient. Unlike wild-type (WT) T-bet, the mutant form of T-bet from this patient did not inhibit the production of Th2 cytokines, including IL-4, IL-5, IL-9, and IL-13, when overexpressed in T helper 2 (Th2) cells. Moreover, Herpesvirus saimiri\u2013immortalized T cells from the patient produced abnormally large amounts of Th2 cytokines, and the patient had markedly high plasma IL-5 and IL-13 concentrations. Finally, the patient\u2019s CD4+ \u03b1\u03b2 T cells produced most of the Th2 cytokines in response to chronic stimulation, regardless of their antigen specificities, a phenotype reversed by the expression of WT T-bet. T-bet deficiency thus underlies the excessive production of Th2 cytokines, particularly IL-5 and IL-13, by CD4+ \u03b1\u03b2 T cells, causing blood eosinophilia and UAI. The MSMD of this patient results from defective IFN-\u03b3 production by innate and innate-like adaptive lymphocytes, whereas the UAI and eosinophilia result from excessive Th2 cytokine production by adaptive CD4+ \u03b1\u03b2 T lymphocytes.<\/jats:p>","DOI":"10.1084\/jem.20202726","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T14:17:58Z","timestamp":1624457878000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":38,"title":["High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4427-2158","authenticated-orcid":true,"given":"Rui","family":"Yang","sequence":"first","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 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