A myeloid sentinel that secretes leukotrienes to activate type 2 immunity

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Project Summary/Abstract Sensing is the obligate first step of any immune response, resulting in activation of early innate signals that direct subsequent adaptive immunity. The sensing of bacteria, viruses, and fungi has been defined in detail, but our understanding of how parasitic worms (helminths) and allergens are detected to initiate “type 2” immunity remains lacking. Group 2 innate lymphoid cells (ILC2s) are among the first immune cells activated in a type 2 response, but they do not directly sense foreign agonists. Instead, host-derived signals from the surrounding tissues activate ILC2s. One such signal is cysteinyl leukotrienes (cysLT), which are required to activate both intestinal and airway ILC2s. Over time, ILC2s are replaced by effector and memory Th2 cells that acquire an ILC2-like transcriptional and epigenetic phenotype. These Th2 cells can be activated by IL-33 in the absence of antigen, but a role for cysLT in driving this innate-like function has not been tested. In the intestine, cysLTs must be produced by epithelial tuft cells, but tuft cells are largely dispensable for airway type 2 inflammation. In Aim 1 of this proposal, we seek to identify the cellular source of cysLTs that activate airway ILC2s during helminth infection. In Aim 2, we test the cell intrinsic role of cysLT signaling in Th2 effector and memory cells. Our studies promise to reveal tissue-specific paradigms for initiation and maintenance of type 2 immunity, thereby suggesting new strategies for therapeutic intervention.