Identification of the Cellular Sentinels for Native Immunogenic Heat Shock Proteins In Vivo

Abstract

Select members of the heat shock proteins (HSPs) family, such as gp96, elicit immune responses specific to their chaperoned peptides. While immunological effects of HSPs on antigen presenting cell (APCs) described to date have largely been demonstrated with cell lines or primary cells in culture, their collective responses in vitro have been consistent with priming immune responses. Here we examine the physiologically relevant APCs in mice that are targeted following vaccination with native, murine HSP and characterize those cells. Gp96 accesses the subcapsular region of the draining lymph node and is internalized predominantly by CD11b+ cells in this locale. Cells acquiring gp96 can transfer protective anti-tumor immunity to naïve mice by actively cross-presenting gp96-chaperoned peptides and providing co-stimulation. Our studies illustrate how HSPs act to alert the immune system of cellular damage and will be of paramount importance in immunotherapy of patients with cancer and infectious disease.

Establishment of Tumor-Associated Immunity Requires Interaction of Heat Shock Proteins with CD91

“…Here we show that the HSP-peptide complex with its receptor CD91 provides such a mechanism. This study is supported by a large body of work in vitro demonstrating the efficient cross-presentation of HSP-chaperoned peptides by a variety of CD91-expressing APCs (7-11,28,33). In our present study, it is clear that upward titration of tumor cell-associated antigen renders the cross-presentation less dependent on the HSP-CD91 pathway.…”

“…Control BMDCs from CD91 +/+ mice secreted IL-1β after stimulation with LPS or gp96, consistent with our previous observations (17,18). We tested the ability of BMDCs to mature in response to gp96 as previously shown (28). BMDCs from CD91 −/− mice failed to upregulate maturation markers CD86 and CD40 in response to incubation with gp96 (Fig.…”

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

“…7b). It was previously shown by our lab that gp96 is passively drained to the subcapsular sinus of lymph nodes, where it is taken up by DCs31. It is possible that higher doses of gp96 are required to diffuse to pDCs, which normally reside within the T-cell zone or pDCs are less sensitive to gp96 and require a higher dose for activation.…”

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

“…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).…”