Noncovalent association with stress protein facilitates cross-priming of CD8+ T cells to tumor cell antigens by dendritic cells.
A viral oncogene carrying well-defined K(b)/D(b)-restricted epitopes was expressed in a heat shock protein (hsp)-associated or nonassociated form in the murine tumor cells P815 and Meth-A. Wild-type SV40 large T-Ag (wtT-Ag) is expressed without stable hsp association; mutant (cytoplasmic cT-Ag) or chimeric (cT272-green fluorescent fusion protein) T-Ag is expressed in stable association with the constitutively expressed, cytosolic hsp73 (hsc70) protein. In vitro, remnants from apoptotic wtT-Ag- or cT-Ag-expressing tumor cells are taken up and processed by immature dendritic cells (DC), and the K(b)/D(b)-binding epitopes T1, T2/3, and T4 of the T-Ag are cross-presented to CTL in a TAP-independent way. DC pulsed with remnants of transfected, apoptotic tumor cells cross-presented the three T-Ag epitopes more efficiently when they processed ATP-sensitive hsp73/cT-Ag complexes than when they processed hsp-nonassociated (native) T-Ag. In vivo, more IFN-gamma-producing CD8+ T cells were elicited by a DNA vaccine that encoded hsp73-binding mutant T-Ag than by a DNA vaccine that encoded native, non-hsp-binding T-Ag. Three- to 5-fold higher numbers of T-Ag (T1-, T2/3-, or T4-) specific, D(b)/K(b)-restricted IFN-gamma-producing CD8+ T cells were primed during the growth of transfected H-2(d) Meth-A/cT tumors than during the growth of transfected Meth-A/T tumors in F(1)(b x d) hosts. Hence, the association of an oncogene with constitutively expressed, cytosolic hsp73 facilitates cross-priming in vitro and in vivo of CTL by DC that process material from apoptotic cells.
Kammerer
Robert
R
Department of Medical Microbiology, University of Ulm, Helmholtzstrasse 8/1, D-89081 Ulm, Germany.
Stober
Detlef
D
Riedl
Petra
P
Oehninger
Claude
C
Schirmbeck
Reinhold
R
Reimann
Jörg
J
D000818:Animals; D017951:Antigen Presentation; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D004705:Endocytosis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019444:Vaccines, DNA
D000952:Antigens, Polyomavirus Transforming; D019496:Cancer Vaccines; D002352:Carrier Proteins; D018984:Epitopes, T-Lymphocyte; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C494372:Hspa8 protein, mouse; D019444:Vaccines, DNA; D007371:Interferon-gamma