Perforin is required for innate and adaptive immunity induced by heat shock protein gp96.
Tumor-secreted gp96-Ig is highly immunogenic and triggers CD8 T cell-mediated tumor rejection. In vivo secreted gp96-Ig and gp96-myc cause NK activation and clonal expansion of specific CD8(+) CTL in wild-type and in Fas-ligand-deficient (gld) mice but not in perforin- (PKO) or IFN-gamma-deficient (GKO) mice. Transfer of perforin-competent NK cells restores the ability of PKO mice to clonally expand CD8 CTL in response to gp96-Ig. The data demonstrate an essential role for perforin-mediated functions in the activation of innate and adaptive immunity by heat shock protein gp96-peptide complexes. Crosspresentation of antigens by heat shock proteins seems to require a perforin-dependent positive feedback loop between NK and DC for both sustained NK activation and clonal CTL expansion. The studies also explain how depressed NK activity in patients with tumors or after viral infections could diminish CTL responses.
Strbo
Natasa
N
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33136, USA.
Oizumi
Satoshi
S
Sotosek-Tokmadzic
Vlatka
V
Podack
Eckhard R
ER
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000008:administration & dosage; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004527:Egg Proteins / Q000008:administration & dosage / Q000276:immunology; D005246:Feedback; D006360:Heat-Shock Proteins / Q000276:immunology*; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins
D000941:Antigens; D000951:Antigens, Neoplasm; D004527:Egg Proteins; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; C110366:OVA-8; D010446:Peptide Fragments; D052899:Pore Forming Cytotoxic Proteins; C052646:sarcoma glycoprotein gp96 rejection antigens; D054353:Perforin; D007371:Interferon-gamma; D010047:Ovalbumin