Cell intrinsic Wnt4 influences cDC fate determination to suppress Type 2 immunity

We demonstrate that Wnt4, a beta-catenin independent Wnt ligand, is produced by both hematopoietic and non-hematopoietic cells and is both necessary and sufficient for pre-cDC1/cDC1 maintenance. Whereas BM cDC precursors undergo phosphoJNK/c-Jun activation upon Wnt4 treatment, loss of cDC Wnt4 in CD11cCreWnt4flox/flox mice impaired differentiation of CD24+, Clec9A+, CD103+ cDC1 compared to CD11cCre controls. Conversely, sc-RNAseq analysis of BM revealed a 2-fold increase in cDC2 gene signature genes and flow cytometry demonstrated increased numbers of SIRP-a + cDC2 amid lack of Wnt4. Increased cDC2 numbers due to CD11c-restricted Wnt4 deficiency increased interleukin 5 production, group 2 innate lymphoid cell (ILC2) expansion, and host resistance to the hookworm parasite Nippostrongylus brasiliensis. Collectively, these data uncover a novel and unexpected role for Wnt4 in cDC subset differentiation and Type 2 immunity. Overall design: Single-cell RNA-seq in CD11c+ cells isolated from bone marrow in WT and CD11cCre-Wnt4flox/flox KO mice