IRF4 amplifies Th2 responses through inhibition of Il31 expression

ABSTRACT: Immune responses that control helminths and other parasites rely on type 2 CD4 T (Th2) cell cytokines IL-4, IL-5, and IL-13. IL-31 is an understudied cytokine that limits the magnitude of type 2 inflammation in skin. Here we examined how Il31 deficiency alters lung and gut immune responses to helminth Nippostrongylus brasiliensis (Nb). Versus controls, Il31-deficient mice infected with Nb had fewer intestinal worms plus increased GATA3+ and IL-13+ Th2 cells in small intestine. CD4+ T cells were the predominant producers of IL-31 in both lung and gut, as identified in a newly generated Il31 reporter mouse. To identify pathways that regulate Il31 transcription, we conducted a pooled loss-of-function CRISPR screen in mouse Th2 cells. We identified calcium sensor Stim1 as an Il31 activator, and Irf4, a transcription factor that positively regulates IL-4/IL-13, as an Il31 repressor. Irf4 deletion increased IL-31 production in mouse and human primary Th2 cells. In vivo, selective deletion of Irf4 in Il31 expressing cells increased worm burden, indicating that Irf4 supports type 2 responses by limiting IL-31 and positively regulating canonical type 2 cytokines in IL-31-producing T cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE283242 | GEO | 2025/11/27

REPOSITORIES: GEO