GSE116842
DUSP10 constrains innate IL-33-mediated cytokine production in ST2hi memory-type pathogenic Th2 cells
Memory CD4+ T helper (Th) cells are crucial for acquired immunity and protection from infectious microorganisms, and also drive pathogenesis of chronic inflammatory diseases, such as asthma.  ST2hi memory-type Th2 cells have been identified as a pathogenic subpopulation capable of directly inducing eosinophilic airway inflammation.  These ST2hi pathogenic Th2 cells produce large amounts of IL-5 upon stimulation via their TCR, but not in response to IL-33.  In contrast, IL-33 alone induces cytokine production in ST2+ group 2 innate lymphoid cells (ILC2).  We investigated the molecular mechanism that controls the innate function of IL-33-induced cytokine production, and identified a MAPK phosphatase Dusp10, as a key negative regulator of IL-33–induced cytokine production in Th2 cells.  We found that Dusp10 is expressed by ST2hi pathogenic Th2 cells but not by ILC2, and Dusp10 expression inhibits IL-33-induced cytokine production by preventing GATA3 activity through inhibition of p38 MAPK phosphorylation.  Strikingly, deletion of Dusp10 rendered ST2hi Th2 cells able to directly respond to IL-33 exposure and produce IL-5. Thus, DUSP10 constrains IL-33–induced cytokine production in ST2hi pathogenic Th2 cells by controlling p38-mediated GATA3 function. Overall design: Functions of Dusp10, a family of dual specificity protein phosphatase, are assessed by RNA-seq.