Identifying the expression and function of Blimp-1 in ILC2s in allergic asthma

Abstract Allergic asthma is driven by type 2 inflammation from Th2 cell and Type 2 innate lymphoid cells (ILC2s). We recently demonstrated a critical role for Blimp-1, a transcriptional repressor, in Th2 cells to promote allergic asthma. However, the expression and function of Blimp-1 in ILC2s remains undefined. Using genetically modified mouse strains that report Blimp-1 expression via YFP, we surveyed Blimp-1 expression in allergic asthma and other type 2 immune models across various tissues. We found that Blimp-1 is induced in ILC2s in the lung in response to the typical alarmins IL-33 and IL-25, as well as house dust mite (HDM). However, ILC2 activation did not upregulate Blimp-1 in the skin or gut in response to peanut allergen, suggesting a tissue-specific requirement for Blimp-1 in ILC2s. IL-33, as known to be a potent activator of ILC2s, was not required for Blimp-1 expression upon HDM stimulation. Interestingly, IL-10, a potent driver of Blimp-1 in Th2 cells, induced Blimp-1 expression in ILC2s, suggesting IL-10 but not IL-33 may be important for a Blimp-1+ ILC2 state. Intriguingly, Blimp-1 expression did not correlate with cytokine production, potentially representing a unique functional state of ILC2 cells that are high for Blimp-1. To evaluate Blimp-1 function, we deleted Blimp-1 in ILC populations using IL-7Ra Cre crossed to Blimp-1 floxed mice and generated mixed bone marrow chimeras with IL-7Ra Cre control donors. Blimp-1 knockout ILC2s in response to HDM exhibited an alteration in markers of ILC2 activation including ST2, KLRG1 and GATA3, suggesting Blimp-1 plays a role in promoting ILC2 differentiation. Collectively, our study has identified a lung-specific state of ILC2s expressing Blimp-1 that are found in a model of allergic asthma.