The Quality Of Heat Shock Protein-Mediated Responses Is Determined By The Antigen Presenting Cell

Abstract Immunization with Heat shock proteins (HSPs) elicits a spectrum of immune responses including non-antigen specific immunoregulatory responses and proinflammatory antigen specific responses. While some of the aspects of these mechanisms have been determined, many questions remain. HSPs interact with their receptor, CD91, which is expressed on the surface of antigen presenting cells (APCs). In response to HSPs, APCs upregulate expression of costimulatory molecules, release cytokines, and cross-present HSP-chaperoned peptides. This culminates in activation of T and NK cells, which are both required for an optimal Th1 response. We have uncovered unique signaling cascades in macrophages (MΦ), conventional dendritic cells (cDCs), and plasmacytoid dendritic cells (pDCs) which include NF-kB and p38 MAPK and result in different downstream immune responses. In MΦ, p38 MAPK mediates phosphorylation of STAT1 at both phosphorylation sites, Y701 and S737. Phosphorylation of STAT1 leads to the secretion of CXCL10 and downstream activation of NK cells. In contrast, cDCs fail to phosphorylate STAT1 at Y701, produce reduced amounts of CXCL10 and do not activate NK cells, thus yielding sub-optimal T cell responses. Alternatively, activation of pDCs by HSPs induces surface expression of NRP1. NRP1 expression allows for engagement and activation of regulatory T cells and downstream suppression of immune responses. Collectively, our data demonstrates that targeting HSPs to particular APCs is critical in elucidating the desired immune response and needs to be considered in future clinical applications.