Intracellular HSP70L1 inhibits human dendritic cell maturation by promoting suppressive H3K27me3 and H2AK119Ub1 histone modifications.

Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and behaviors. However, the epigenetic mechanisms that regulate human dendritic cell (DC) differentiation and development remain poorly understood. Our previous studies show that extracellular heat shock protein 70-like protein (HSP70L1) is a potent adjuvant of Th1 responses via stimulating DCs when released from cells; however, the role of intracellular HSP70L1 in DC differentiation and maturation remains unknown. Herein, we demonstrate that intracellular HSP70L1 inhibits human DC maturation by suppressing MHC and costimulatory molecule expression, in contrast to the adjuvant activity of extracellular HSP70L1. The stability of intracellular HSP70L1 is dependent on DNAJC2, a known epigenetic regulator. Mechanistically, intracellular HSP70L1 inhibits the recruitment of Ash1l to and maintains the repressive H3K27me3 and H2AK119Ub1 modifications on the promoter regions of costimulatory, MHC and STAT3 genes. Thus, intracellular HSP70L1 is an inhibitor of human DC maturation. Our results provide new insights into the epigenetic regulation of cell development by intracellular HSP70L1.