HSPs drive dichotomous T-cell immune responses via DNA methylome remodelling in antigen presenting cells.

Immune responses primed by endogenous heat shock proteins, specifically gp96, can be varied, and mechanisms controlling these responses have not been defined. Immunization with low doses of gp96 primes T helper type 1 (Th1) immune responses, whereas high-dose immunization primes responses characterized by regulatory T (Treg) cells and immunosuppression. Here we show gp96 preferentially engages conventional and plasmacytoid dendritic cells (pDCs) under low and high doses, respectively, through CD91. Global DNMT-dependent epigenetic modifications lead to changes in protein expression within these antigen-presenting cells. Specifically, pDCs upregulate neuropilin-1 to enable the long term interactions of pDCs with Treg cells, thereby enhancing suppression of Th1 anti-tumour immunity. Our study defines a CD91-dependent mechanism through which gp96 controls dichotomous immune responses relevant to the therapy of cancer and autoimmunity.