Epigenetic stabilization of DC and DC precursor classical activation by TNFα contributes to protective T cell polarization

Epigenetic modifications play critical roles in inducing long-lasting immunological memory in innate immune cells, termed trained immunity. Whether similar epigenetic mechanisms regulate dendtritic cell (DC) function to orchestrate development of adaptive immunity remains unknown. We report that DCs matured with IFN gamma and TNF alpha or matured in the lungs during invasive fungal infection with endogenous TNF alpha acquired a stable TNF alpha-dependent DC1 program, rendering them resistant to both antigen- and cytokine-induced alternative activation. TNF alpha-programmed DC1 had increased association of H3K4me3 with DC1 gene promoter regions. Furthermore, MLL1 inhibition blocked TNF alpha-mediated DC1 phenotype stabilization. During IFI, TNF alpha-programmed DC1s were required for the development of sustained T(H)1/T(H)17 protective immunity, and bone marrow pre-DCs exhibited TNF alpha-dependent preprogramming, supporting continuous generation of programmed DC1 throughout the infection. TNF alpha signaling, associated with epigenetic activation of DC1 genes particularly via H3K4me3, critically contributes to generation and sustenance of type 1/17 adaptive immunity and the immune protection against persistent infection.