IL-25 simultaneously elicits distinct populations of innate lymphoid cells and multipotent progenitor type 2 (MPP^type2) cells

The predominantly epithelial cell-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) can promote CD4+ Th2 cell-dependent immunity, inflammation, and tissue repair at barrier surfaces through the induction of multiple innate immune cell populations. IL-25 and IL-33 were previously shown to elicit four innate cell populations, named natural helper cells, nuocytes, innate type 2 helper cells, and multipotent progenitor type 2 (MPP^type2) cells, now collectively termed group 2 innate lymphoid cells (ILC2). In contrast to other types of ILC2, MPP^type2 cells exhibit multipotent potential and do not express T1/ST2 or IL-7R?, suggesting that MPP^type2 cells may be a distinct population. Here, we show that IL-33 elicits robust ILC2 responses, whereas IL-25 predominantly promotes MPP^type2 cell responses at multiple tissue sites with limited effects on ILC2 responses. MPP^type2 cells were distinguished from ILC2 by their differential developmental requirements for specific transcription factors, distinct genome-wide transcriptional profile, and functional potential. Furthermore, IL-25- induced MPP^type2 cells promoted Th2 cytokine-associated inflammation after depletion of ILC2. These findings indicate that IL-25 simultaneously elicits phenotypically and functionally distinct innate lymphoid- and nonlymphoid-associated cell populations and implicate IL-25- elicited MPP^type2 cells and extramedullary hematopoiesis in the promotion of Th2 cytokine responses at mucosal surfaces.