Anti-tumor MHC class Ia-unrestricted CD8 T cell cytotoxicity elicited by the heat shock protein gp96.
In Xenopus as in mammals, gp96 stimulates MHC-restricted cellular immunity against chaperoned minor histocompatibility (H) antigens (Ag). In adult Xenopus, gp96 also elicits peptide-specific effectors against MHC class Ia-negative 15/0 tumors. To determine whether gp96 can generate functionally heterogeneous CD8+ effectors (CTL that kill MHC class Ia+ minor H-Ag-disparate lymphoblasts and MHC class Ia- tumor targets), LG-6 isogenetic frogs were immunized with gp96 purified either from MHC-identical but minor H-Ag-disparate LG-15 normal tissues or from the MHC class Ia-negative 15/0 tumor line (derived from LG-15 frogs). LG-15 normal liver-derived gp96 did not induce detectable CD8+ in vitro killing against 15/0 tumor cells. However, 15/0-derived gp96 did induce killing against both MHC class Ia+ LG-15 lymphoblasts and the MHC class Ia- 15/0 tumor, but not against another MHC class Ia- tumor (B3B7) or against LG-6 lymphoblasts. Tumor killing was better when 15/0 rather than normal LG-15 irradiated stimulators were used, but in vitro stimulation without prior in vivo immunization was ineffective. These data suggest that (1) 15/0-derived gp96 chaperones minor H-Ag shared with normal LG-15 lymphocytes and elicits MHC-restricted CTL, and (2) 15/0-derived gp96, but not normal liver-derived gp96, generates CD8+ effectors that kill 15/0 tumor cells in the absence of MHC class Ia expression.
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Ana
A
Goyos
Nicholas
N
Cohen
Jennifer
J
Gantress
Jacques
J
Robert
D000818:Animals; D000951:Antigens, Neoplasm / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology; D015778:Minor Histocompatibility Antigens / Q000502:physiology; D014981:Xenopus
D000951:Antigens, Neoplasm; D000949:Histocompatibility Antigens Class II; D015778:Minor Histocompatibility Antigens; C052646:sarcoma glycoprotein gp96 rejection antigens