Distinct 3D remodeling of <i>Il4-Il13-Il5</i>loci mediates differential type 2 responses in innate versus adaptive lymphocytes

Abstract The type 2 cytokines, interleukin (IL)-4, IL-5 and IL-13 reside within a tandem multi-gene cluster in mammals. These cytokines represent the hallmark of immune responses controlling parasites, promoting tissue repair as well causing allergic diseases. Both innate adaptive lymphocytes secrete with discordant production spectra. However, how those two related but distinct configure extended cytokine loci elicit selective output this cassette genes is not understood. Here, we took holistic structural functional view locus before after activation, comparing (ILC2) (Th2) to understand mechanisms underlying their distinctive programs. Rapid induction dominates ILC2, whereas IL-4 does so Th2 cells. Using high-resolution chromatin conformation capture found that global cellular architecture remained constant, rapidly remodeled. In Il13and Il5loci were aligned proximity Il4locus was insulated. cells, Il4and Il13positioned while Il5locus distal. Select REs separately deleted mice confirm cell-type specific activation-dependent roles vivo. Thus, contrary premise plays minimal role steady-state gene induction, signal-dependent remodeling 3D configuration underlies outputs ILC2s versus