Abstract
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.
Highlights
Immune responses primed by endogenous heat shock proteins, gp[96], can be varied, and mechanisms controlling these responses have not been defined
CD91 serves as a signalling receptor such that when it is bound by HSPs, intracellular signalling pathways activate nuclear factor (NF)-kB and drive the release of pro-inflammatory cytokines and upregulate co-stimulatory molecules CD86 and CD40 on conventional dendritic cells[8,9]
We show here that extracellular gp[96] differentially engages CD91 þ antigenpresenting cells (APCs) populations when introduced at low dose versus high dose, driving divergent DNA methylation programs in the respective APCs via activation of DNA methyltransferases (DNMTs)
Summary
Immune responses primed by endogenous heat shock proteins, gp[96], can be varied, and mechanisms controlling these responses have not been defined. Of the total number of cells in the lymph node, 0.055% were gp[96] þ pDCs (CD11clow/ þ CD11b À B220 þ PDCA þ ) when mice were administered high-dose gp96A488, significantly higher that 0.005% with low-dose gp96A488 immunization (Fig. 2d). The percentage of Nrp[1] þ pDCs was significantly increased when mice were immunized with high dose but not low-dose gp[96] (Fig. 3g).
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