DUSP10 constrains innate IL-33-mediated cytokine production in ST2hi memory-type pathogenic Th2 cells

Abstract

ST2hi memory-type Th2 cells are identified as a pathogenic subpopulation in eosinophilic airway inflammation. These ST2hi pathogenic Th2 cells produce large amount of IL-5 upon T cell receptor stimulation, but not in response to IL-33 treatment. By contrast, IL-33 alone induces cytokine production in ST2+ group 2 innate lymphoid cells (ILC2). Here we show that a MAPK phosphatase Dusp10 is a key negative regulator of IL-33-induced cytokine production in Th2 cells. In this regard, Dusp10 is expressed by ST2hi pathogenic Th2 cells but not by ILC2, and Dusp10 expression inhibits IL-33-induced cytokine production. Mechanistically, this inhibition is mediated by DUSP10-mediated dephosphorylation and inactivation of p38 MAPK, resulting in reduced GATA3 activity. The deletion of Dusp10 renders ST2hi Th2 cells capable of producing IL-5 by IL-33 stimulation. Our data thus suggest that DUSP10 restricts IL-33-induced cytokine production in ST2hi pathogenic Th2 cells by controlling p38-GATA3 activity.

A Truncated Form of HpARI Stabilizes IL-33, Amplifying Responses to the Cytokine

“…To assess whether HpARI_CCP1/2 could replicate the inhibition of IL-33-dependent responses seen with full-length HpARI, we administered HpARI or HpARI_CCP1/2 together with Alternaria allergen and OVA protein and assessed type 2 immune responses after OVA challenge 2 weeks later (Figure 2A). While HpARI suppressed allergic reactivity in this model (as shown previously (8)), HpARI_CCP1/2 had the opposite effect, increasing BAL and lung eosinophil, and lung ILC2 and ICOS + ST2 + Th2 cell numbers (18) (Figure 2A and Supplementary Figure 1).…”

Epithelial cell–derived cytokines: more than just signaling the alarm

“…In helminth infection, an ST2 + subset of memory Th2 cells was required to drive production of major basic protein (MBP) by eosinophils after infection (123,124). While ILC2 and pathogenic memory Th2 cell populations both express high levels of ST2 and share transcriptional and epigenetic profiles (126), Th2 cells but not ILC2s express DUSP10, a phosphatase that can negatively regulate IL-33-mediated cytokine production (127). It is now also clear that IL-33 can promote the induction and function of Tregs in a variety of settings (103,(128)(129)(130).…”

Epigenetic and Transcriptional Regulation in the Induction, Maintenance, Heterogeneity, and Recall-Response of Effector and Memory Th2 Cells

“…ILC2 cells can produce IL-5 in response to IL-33 stimulation whereas Tpath2 cells need TCR stimulation to produce IL-5. Dusp10, which is highly expressed in Tpath2 cells compared to ILC2 cells, was found to be involved in inhibiting IL-33-dependent IL-5 production in Tpath2 cells (89). Thus, the Dusp10-mediated suppression of IL-5 may explain the difference in responsiveness to IL-33 between Tpath2 and ILC2.…”