The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of its receptor

Peptides associated with the heat shock protein gp96 induce a specific T ce ll response against cells from which gp96 is isolated. Recently, we have sh own that gp96 binds to a yet unknown receptor present on dendritic cells (D C) and that receptor-mediated uptake is required for cross-presentation of gp96-associated peptides by DC. We now describe that gp96 mediates maturati on of DC as determined by up-regulation of MHC class II and CD86 molecules, secretion of the cytokines IL-12 and TNF-alpha and enhanced T cell stimula tory capacity. Heat-denatured gp96 is not able to induce DC maturation and cytokine secretion. Furthermore, we show that mature DC are no longer able to bind gp96 molecules. Hence, the gp96 receptor is down-regulated on matur e DC, suggesting that this receptor behaves similar to other receptors invo lved in antigen uptake like the scavenger receptor CD36, the mannose recept or or the integrins alpha(V)beta(3) and alpha(V)beta(5). Together, our find ings provide an additional explanation for the remarkable immunogenicity of gp96 as a cross-priming antigen carrier and direct activator of DC.