Adenosine metabolized from extracellular ATP promotes type 2 immunity through triggering A2BAR signaling on intestinal epithelial cells

Abstract

Abstract Intestinal nematode infections trigger potent type 2 immune responses, although the mechanisms that initiate these host protective responses against multicellular parasites remain uncertain. We have previously reported that A2BAR deficient mice (A2BAR−/−) have an impaired type 2 immune response and delayed helminth expulsion during Heligmosomoides polygyrus bakeri (Hpb) infection. However, the cell types expressing A2BAR receptors that participate in this initiation and how the adenosine-A2BAR axis drives memory type 2 immune responses in helminth infections remains unknown. We now report that mice lacking A2BAR specifically on intestinal epithelial cells (VillinCre-A2BARfl/fl), but not on myeloid cells (LysMCre-A2BARfl/fl) show increased worm metabolism and delayed worm expulsion after Hpb secondary inoculation. We further show, the transfer of Hpb primed CD4+ T cells from WT but not from VillinCre-A2BARfl/fl can rescue the impaired immune response in recipient VillinCre-A2BARfl/fl mice. Moreover, the transfer of Hpb primed CD4+ T cells from WT but not from IL-4−/− mice into IL-4−/− mice rescued the protective memory type 2 immune response. During the primary response, type 2 immunity was dependent on epithelial A2BAR signaling as early as 24 hours after inoculation and was associated with marked increases in eATP production. Furthermore, mice lacking CD39 exhibited similarly impaired type 2 immunity to Hpb, indicating that extracellular ATP is metabolized to adenosine, which then acts as an essential endogenous danger signal. Our data thus demonstrate a key role for intestinal epithelial cell-specific A2BAR signaling in the development of host protective CD4+ IL-4 expressing memory T cells during helminth infection.