The transcription factor Zeb1 controls homeostasis and function of type 1 conventional dendritic cells

Abstract

Abstract Type 1 conventional dendritic cells (cDC1s) are the most efficient cross-presenting cells that induce protective cytotoxic T cell response. However, the regulation of their homeostasis and function is incompletely understood. Here we observed a selective reduction of splenic cDC1s in mice with Zeb1 deficiency in dendritic cells, due to excessive cell death, rendering mice higher resistance to Listeria infection. Moreover, cDC1s from other sources of Zeb1-deficient mice displayed impaired cross-presentation of exogenous antigens, resulting in compromised antitumor CD8+ T cell responses. Mechanistically, Zeb1 facilitated the production of phagosomal reactive oxygen species by repressing the expression of microRNA-96 that targeted Cybb mRNA of NADPH oxidase Nox2. Consequently, loss of Zeb1 in cDC1s diminished phagosomal membrane rupture that permits antigen export to the cytosol. Cybb re-expression in Zeb1-deficient cDC1s fully restored the defective cross-presentation while microRNA-96 overexpression in Zeb1-sufficient cDC1s inhibited cross-presentation. Therefore, our results identify a novel Zeb1-microRNA-96-Cybb pathway that controls cross-presentation in cDC1s and uncover an essential role of Zeb1in cDC1 homeostasis.