Egr2-dependent Mo-DCs regulate immunosuppressive NK cells, promoting neutrophil-mediated protective immunity against acute Listeria infection

The interactions between dendritic cells (DCs) and other innate immune cells during acute bacterial infection remain poorly understood. To investigate this cross-talk, we generated CD11c-cre-mediated early growth response gene-2 knockout (Egr2^cKO) mice and used an acute Listeria monocytogenes (LM) infection model. In wild-type mice, LM infection induced the generation of monocyte-derived DCs (Mo-DCs), which suppressed the conversion of natural killer (NK) cells into immunosuppressive NK cells, while Mo-DC-derived TNF-α enhanced neutrophil (NP) activity to control infection. In contrast, Egr2^cKO mice exhibited significantly increased susceptibility to LM infection compared with their Egr2-floxed wild-type littermates, primarily due to a deficiency in Mo-DCs. Instead, monocytes in Egr2^cKO mice differentiated predominantly into macrophages, which expressed interleukin-15/interleukin-15R and promoted the expansion of immunosuppressive CD11b^lowCD27⁺TIGIT⁺ NK cells. These NK cells produced TGF-β, thereby suppressing NP-mediated NETosis. In vivo depletion of NK cells in Egr2^cKO mice partially restored protective immunity, whereas depletion of NPs further exacerbated susceptibility to LM infection. In conclusion, our study demonstrates that Egr2-dependent Mo-DCs play a pivotal role in host defense against acute LM infection by restraining the expansion of immunoregulatory NK cells and enhancing TNF-α-mediated NPs NETosis. These findings highlight the Mo-DC/NK/NP immune axis as a key element of the innate immune response to acute bacterial infection.