Rapid tolerization of virus-activated tumor-specific CD8+ T cells in prostate tumors of TRAMP mice.
To study T cell responses to tumors in an autochthonous model, we expressed a CD8 T cell epitope SIYRYYGL (SIY) in the prostate of transgenic adenocarcinoma (TRAMP) mice (referred to as TRP-SIY), which spontaneously develop prostate cancer. Naïve SIY-specific CD8 T cells adoptively transferred into TRP-SIY mice became tolerized in the prostate draining lymph nodes. Vaccination of TRP-SIY mice intranasally with influenza virus that expresses the SIY epitope resulted in generation of SIY-specific effector T cells in the lung-draining lymph nodes. These effector T cells expressed TNFalpha and IFNgamma, eliminated SIY peptide-loaded target cells in vivo, and infiltrated prostate tumors, where they rapidly lost the ability to produce effector cytokines. A population of these T cells persisted in prostate tumors but not in lymphoid organs and could be induced to re-express effector functions following cytokine treatment in vitro. These findings suggest that T cells of a given clone can be activated and tolerized simultaneously in different microenvironments of the same host and that effector T cells are rapidly tolerized in the tumors. Our model provides a system to study T cell-tumor interactions in detail and to test the efficacy of cancer immunotherapeutic strategies.
Bai
Ailin
A
Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Higham
Eileen
E
Eisen
Herman N
HN
Wittrup
K Dane
KD
Chen
Jianzhu
J
D000230:Adenocarcinoma / Q000276:immunology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D045142:Cross-Priming / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D009975:Orthomyxoviridae / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology; D017430:Prostate-Specific Antigen / Q000276:immunology; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000821:virology*; D051381:Rats; D014611:Vaccination
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D017430:Prostate-Specific Antigen