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

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.

Cutting Edge: The Heat Shock Protein gp96 Activates Inflammasome-Signaling Platforms in APCs

“…and Supplemental Fig.1J, we show that NLRP3 induction by gp96 was dependent on NF-κB but not p38 MAPK. These signaling pathways are consistent with earlier observations (1,6). …”

“…Although there has been a great interest in harnessing these Th1 responses for the immunotherapy of cancer and infectious disease (4), the complexities of cytokine release by APCs have not yet been fully investigated. Importantly, the distinct signaling pathways and final repertoire of cytokines released is dependent on the APC that is engaged by the HSP (1,2,5,6), and the contribution of other signals in the microenvironment (1). These mechanisms allow HSPs to prime Th1 (3), Th17 (1) or Treg responses (6,7).…”

“…Importantly, the distinct signaling pathways and final repertoire of cytokines released is dependent on the APC that is engaged by the HSP (1,2,5,6), and the contribution of other signals in the microenvironment (1). These mechanisms allow HSPs to prime Th1 (3), Th17 (1) or Treg responses (6,7). The release of IL-1β from a variety of APCs, including DCs and macrophages, in response to HSPs, has conspicuously lacked a basic characterization even though this seminal observation was made over 17 years ago (2).…”

Environmental cues received during development shape dendritic cell responses later in life

“…Fcgr1 encodes the high affinity immunoglobulin gamma Fc receptor I (FCGR1), which mediates internalization of antigen-IgG complexes and DC cross presentation [ 67 , 68 ]. Lrp1 encodes a scavenger receptor called low density lipoprotein receptor-related protein 1 or LRP1, which aids in the internalization of antigen-heat shock protein complexes [ 69 – 71 ]. Both FCGR1 and LRP1 play a role in cross-presentation of exogenous antigen in the context of MHCI on DCs [ 67 – 72 ].…”

Endoplasmic reticulum in health and disease: the 12th International Calreticulin Workshop, Delphi, Greece

“…Robert Binder (Pittsburgh, USA) presented recent findings from his group regarding the regulation of the signalling cascades within antigen‐presenting cells, triggered by ER heat‐shock proteins (HSP) . More specifically, they have shown that when released from aberrant cells, these HSPs engage their receptor CD91 expressed on antigen‐presenting cells.…”