Transcription factor Etv6 controls functional differentiation of cross-presenting classical dendritic cells [ATAC-Seq]

An IRF8-dependent subset of classical dendritic cells (cDCs), termed DC1, effectively cross-primes CD8+ T cells and facilitates antitumor T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function. We report that like HSPC, cDCs express Etv6 but not its antagonist ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow reduced the generation of DC1-like cells in vitro and the differentiation of DC1 in vivo, including the loss of signature marker CD8a. Global expression and chromatin profiling of Etv6-deficient DCs revealed impaired lineage identity of DC1, including the reduction of cDC signature and upregulation of pDC signature. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and tumor-specific CD8+ T cell responses. These results identify Etv6 as a regulator of DC1 differentiation and functional fitness that indirectly facilitates T cell cross-priming and antitumor immunity. Examination of chromatin accessibility profiles of Etv6-deficient dendritic cell subtypes