UCSF

Th2 cells are specialized to control helminths and other parasites. The protective response induced by Th2 cells, known as the type 2 immune response, is driven by their secretion of the canonical cytokines IL-4, IL-5, and IL-13. IL-31 is a lesser known Th2 cytokine whose interactions with its receptor, IL-31RAa/OSMRb limit the magnitude of type 2 responses in the skin. Little is known about the molecular regulation of IL-31 expression. To define how IL-31 modulates immune responses in tissues other than skin we used the Nippostronglyus bransiliens (N.b.) model of type 2 immunity. Compared to wildtype controls, IL31-deficient mice infected with N.b. had a lower intestinal worm burden and increased GATA3 and IL-13 expressing Th2 cells in the intestine. CD4+ T cells were the predominant producers of IL-31 in the lung and intestine, as indicated by a newly generated IL31 reporter mouse. To identify pathways that control Il31 transcription in mouse Th2 cells, we conducted a CRISPR-based screen. This screen identified the calcium sensor STIM1 as an activator, and IRF4, a transcription factor that positively regulates IL-4 and IL-13 production, as a repressor of IL31. IRF4 deletion increased IL-31 production in both mouse and human primary Th2 cells. In vivo, conditional deletion of IRF4 only in IL31 expressing cells increased intestinal N.b. worm burden, indicating that IRF4 supports type 2 responses by limiting IL-31 and positively regulating canonical cytokines in IL-31-producing helper T cells.