title: Calreticulin requires an ancillary adjuvant for the induction of efficient cytotoxic T cell responses.
abstract: Molecular chaperones stimulate the immune system to induce both protective immune responses and therapeutic tumor rejection. However, the underlying basis for this immunogenic activity is not well understood. A variety of chaperones, including calreticulin, hsp70 and grp94, function as vehicles to efficiently traffic associated peptides into professional antigen presenting cells. Importantly, these chaperones have also been proposed to function as adjuvants by stimulating the dendritic cell activation and co-stimulatory responses required to elicit peptide-specific CD8(+) T cell cytolytic activity. The efficacy of chaperone-mediated tumor rejection has been attributed to the ability of chaperones to function in both of these capacities. However, purified calreticulin has not previously been assessed for its ability to elicit DC maturation and, moreover, recent data indicates that it is not efficient at inducing Nf-kappaB activity which often accompanies or stimulates DC maturation. Here we use two complementary methods to produce endotoxin-free calreticulin and demonstrate that it does not measurably mature or activate dendritic cells both in vitro and in vivo. Additionally, a calreticulin/peptide complex required the addition of an exogenous adjuvant to elicit in vivo cytotoxic CD8(+) T cell responses. These data are discussed with respect to current models for chaperone-derived immune responses and in regard to rational vaccine design.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03755, USA.
authors.forename: S Peter
authors.initials: SP
authors.lastname: Bak
authors.forename: Eyal
authors.initials: E
authors.lastname: Amiel
authors.forename: Julie Jo
authors.initials: JJ
authors.lastname: Walters
authors.forename: Brent
authors.initials: B
authors.lastname: Berwin
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D037282:Calreticulin / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology; D007109:Immunity; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000276:immunology; D010455:Peptides / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D037282:Calreticulin; D018832:Molecular Chaperones; D010455:Peptides