Identification of the cellular sentinels for native immunogenic heat shock proteins in vivo.
Select members of the heat shock proteins (HSPs) family, such as gp96, elicit immune responses specific to their chaperoned peptides. Although immunologic effects of HSPs on APCs described to date have largely been demonstrated with cell lines or primary cells in culture, their collective responses in vitro have been consistent with priming immune responses. In this study, we examine the physiologically relevant APCs in mice that are targeted after vaccination with native, murine HSPs, and we characterize those cells. Gp96 accesses the subcapsular region of the draining lymph node, and it is internalized predominantly by CD11b(+) cells in this locale. Cells acquiring gp96 can transfer protective antitumor immunity to naive mice by actively cross-presenting gp96-chaperoned peptides and providing costimulation. Our studies illustrate how HSPs act to alert the immune system of cellular damage and will be of paramount importance in immunotherapy of patients with cancer and infectious disease.
Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261;
Michelle Nicole
MN
Messmer
Joshua
J
Pasmowitz
Laura Elizabeth
LE
Kropp
Simon C
SC
Watkins
Robert Julian
RJ
Binder
D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D039481:CD11b Antigen / Q000378:metabolism; D002460:Cell Line; D006360:Heat-Shock Proteins / Q000008:administration & dosage / Q000276:immunology*; D007114:Immunization; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000276:immunology; D009369:Neoplasms / Q000276:immunology*
D000951:Antigens, Neoplasm; D039481:CD11b Antigen; D006360:Heat-Shock Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; C053387:endoplasmin