Activation of low avidity CTL specific for a self epitope results in tumor rejection but not autoimmunity.
To determine how self-tolerance can alter the ability of the immune system to respond against tumor-associated Ags that are also expressed by normal tissue, we designed experiments in which the same protein was expressed both as a tumor Ag and as a transgene product. Unlike conventional BALB/c mice that rejected renal carcinoma cells transfected with the influenza virus hemagglutinin (Renca-HA), transgenic mice that are tolerant of HA due to its expression as a self-Ag on pancreatic islet beta cells, (Ins-HA mice) supported progressive growth of these tumor cells. However, when Ins-HA mice were immunized with a recombinant strain of vaccinia virus expressing the dominant H-2Kd peptide epitope of HA before receiving Renca-HA cells, they too were able to reject the tumor cells. Rejection of Renca-HA cells by immunized Ins-HA mice was found to be associated with the generation of CTL having much lower avidity for target cells presenting the KdHA epitope than CTL from immunized conventional BALB/c mice. Significantly, we show that self-tolerance to the HA Ag is quantitative rather then absolute, and that vaccination of Ins-HA mice can activate low avidity KdHA-specific CD8+ T cells that are able to reject tumor cells expressing high levels of HA, yet these mice remain tolerant of pancreatic islet beta cells expressing HA.
Morgan
D J
DJ
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Kreuwel
H T
HT
Fleck
S
S
Levitsky
H I
HI
Pardoll
D M
DM
Sherman
L A
LA
D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D006084:Graft Rejection / Q000235:genetics; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism; D006388:Hemagglutinins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009980:Influenza A virus / Q000276:immunology; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D006388:Hemagglutinins; D010446:Peptide Fragments