The histone demethylase KDM5C regulates IRF transcriptional programming impacting dendritic cell population heterogeneity and function (CUT&RUN)

Functional and phenotypic heterogeneity of dendritic cells (DCs) plays a crucial role in facilitating the development of diverse immune responses essential for host protection. We found that KDM5C, a histone lysine demethylase, regulates conventional DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Mice deficient in KDM5C in DCs, have increased proportions of cDC2Bs and cDC1s, which was partly dependent on type I interferon and pDCs. Loss of KDM5C resulted in an increase in Ly6C- pDCs, which, compared to Ly6C+ pDCs, have limited ability to produce type I interferon and can more efficiently stimulate antigen-specific CD8 T cells. KDM5C-deficient DCs have increased expression of inflammatory genes, altered expression of lineage-specific genes, and reduced function. In response to Listeria infection, KDM5C-deficient mice mounted reduced CD8 responses due to decreased antigen presentation by cDC1s. Thus, KDM5C is a key regulator of DC heterogeneity and a critical driver functional properties of DCs.