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.
Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
Satoshi
S
Oizumi
Natasa
N
Strbo
Savita
S
Pahwa
Vadim
V
Deyev
Eckhard R
ER
Podack
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