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High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency


We have described a child suffering from Mendelian susceptibility to mycobacterial disease (MSMD) due to autosomal recessive, complete T-bet deficiency, which impairs IFN-gamma 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+ alphabeta 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+ alphabeta T cells, causing blood eosinophilia and UAI. The MSMD of this patient results from defective IFN-gamma production by innate and innate-like adaptive lymphocytes, whereas the UAI and eosinophilia result from excessive Th2 cytokine production by adaptive CD4+ alphabeta T lymphocytes.

Type Journal
ISBN 1540-9538 (Electronic) 0022-1007 (Linking)
Authors Yang, R.; Weisshaar, M.; Mele, F.; Benhsaien, I.; Dorgham, K.; Han, J.; Croft, C. A.; Notarbartolo, S.; Rosain, J.; Bastard, P.; Puel, A.; Fleckenstein, B.; Glimcher, L. H.; Di Santo, J. P.; Ma, C. S.; Gorochov, G.; Bousfiha, A.; Abel, L.; Tangye, S. G.; Casanova, J. L.; Bustamante, J.; Sallusto, F.
Responsible Garvan Author Prof Stuart Tangye
Published Date 2021-06-30
Published Volume 218
Published Issue 8
Published Pages e20202726
Status Published in-print
DOI 10.1084/jem.20202726
URL link to publisher's version