{"doi":"10.1084/jem.20202726","title":"High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency","abstract":"We have described a child suffering from Mendelian susceptibility to mycobacterial disease (MSMD) due to autosomal recessive, complete T-bet deficiency, which impairs IFN-γ 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-immortalized 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's CD4+ αβ 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+ αβ T cells, causing blood eosinophilia and UAI. The MSMD of this patient results from defective IFN-γ production by innate and innate-like adaptive lymphocytes, whereas the UAI and eosinophilia result from excessive Th2 cytokine production by adaptive CD4+ αβ T lymphocytes.","journal":"The Journal of Experimental Medicine","year":2021,"id":164993,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":37,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.962,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":558865,"name":"Marc Weißhaar","orcid":"0000-0002-7769-1730","position":1,"is_corresponding":false},{"id":218049,"name":"Federico Mele","orcid":"0000-0003-0455-4687","position":2,"is_corresponding":false},{"id":672535,"name":"Ibtihal Benhsaien","orcid":"0000-0001-5727-9629","position":3,"is_corresponding":false},{"id":104144,"name":"Karim Dorgham","orcid":"0000-0001-9539-3203","position":4,"is_corresponding":false},{"id":558867,"name":"Jing Han","orcid":"0000-0003-2307-438X","position":5,"is_corresponding":false},{"id":478716,"name":"Carys A. 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