Molecular and cellular requirements for enhanced antigen cross-presentation to CD8 cytotoxic T lymphocytes.
MHC class I-mediated cross-priming of CD8 T cells by APCs is critical for CTL-based immunity to viral infections and tumors. We have shown previously that tumor-secreted heat shock protein gp96-chaperoned peptides cross prime CD8 CTL that are specific for genuine tumor Ags and for the surrogate Ag OVA. We now show that tumor-secreted heat shock protein gp96-chaperoned peptides enhance the efficiency of Ag cross-priming of CD8 CTL by several million-fold over the cross-priming activity of unchaperoned protein alone. Gp96 also acts as adjuvant for cross-priming by unchaperoned proteins, but in this capacity gp96 is 1000-fold less active than as a peptide chaperone. Mechanistically, the in situ secretion of gp96-Ig by transfected tumor cells recruits and activates dendritic cells and NK cells to the site of gp96 release and promotes CD8 CTL expansion locally. Gp96-mediated cross-priming of CD8 T cells requires B7.1/2 costimulation but proceeds unimpeded in lymph node-deficient mice, in the absence of NKT and CD4 cells and without CD40L. Gp96-driven MHC I cross-priming of CD8 CTL in the absence of lymph nodes provides a novel mechanism for local, tissue-based CTL generation at the site of gp96 release. This pathway may constitute a critically important, early detection, and rapid response mechanism that is operative in parenchymal tissues for effective defense against tissue damaging antigenic agents.
Oizumi
Satoshi
S
Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
Strbo
Natasa
N
Pahwa
Savita
S
Deyev
Vadim
V
Podack
Eckhard R
ER
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000172:deficiency / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D003429:Cross Reactions / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008223:Lymphoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D015704:CD4 Antigens; C497965:Cd86 protein, mouse; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D011993:Recombinant Fusion Proteins; C052646:sarcoma glycoprotein gp96 rejection antigens; D023201:CD40 Ligand