The heat shock protein gp96: a receptor-targeted cross-priming carrier andactivator of dendritic cells

Heat shock proteins like gp96 (grp94) are able to induce specific cytotoxic T-cell (CTL) responses against cells from which they originate and are cur rently studied in clinical trials for use in immunotherapy of tumors. We ha ve recently demonstrated that gp96 binds to at least one yet unidentified r eceptor restricted to antigen-presenting cells (APCs) like dendritic cells (DCs) but not to T cells. Moreover we have shown, that for CTL activation b y gp96-chaperoned peptides receptor-mediated uptake of gp96 by APCs is requ ired. Lately, we have discovered a second function of gp96 when interacting with professional APCs. Gp96 is able to mediate maturation of DCs as deter mined by upregulation of MHC class II, CD86 and CD83 molecules, secretion o f pro-inflammatory cytokines IL-12 and TNF-alpha and enhanced T-cell simula tory capacity. Furthermore, the gp96 receptor(s) are down-regulated on matu re DCs, suggesting that the gp96 receptor(s) behave similar to other endocy tic receptors like CD36, mannose receptor etc. Our findings now provide add itional evidence for the remarkable immunogenicity of gp96: first, the exis tence of specific gp96 receptors on APCs and second, the capacity to activa te dendritic cells which is strictly required to enable these highly sophis ticated APCs to prime CTL responses.