Tunable heat shock protein-mediated NK cell responses are orchestrated by STAT1 in Antigen Presenting Cells.

The release of Heat Shock Proteins (HSPs) from aberrant cells can initiate immune responses following engagement of the HSPs with antigen presenting cells (APCs). This is an important mechanism for cancer immunosurveillance and can also be modeled by vaccination with HSPs through various routes, targeting specific APCs expressing the HSP receptor CD91. Immunological outcomes can be varied as a result of the broad expression of CD91 in different dendritic cell and macrophage populations.

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.

Phenotypically distinct helper NK cells are required for gp96-mediated anti-tumor immunity.

A number of Heat Shock Proteins (HSPs), in the extracellular environment, are immunogenic. Following cross-presentation of HSP-chaperoned peptides by CD91(+) antigen presenting cells (APCs), T cells are primed with specificity for the derivative antigen-bearing cell. Accordingly, tumor-derived HSPs are in clinical trials for cancer immunotherapy.