Transforming growth factor-beta-mediated signaling in T lymphocytes impacts on prostate-specific immunity and early prostate tumor progression.
T cells are in general tolerant of prostate-specific tumor antigens. That prostate tumor tissue makes transforming growth factor-beta (TGFbeta) is thought to play a role in the induction of T-cell tolerance within the host and to contribute to tumor progression itself. Here we sought to investigate the influence of TGFbeta signaling on prostate antigen-specific T-cell responses as well as prostate tumorogenesis in an autochthonous murine model of the disease. The response of naive and activated ovalbumin (OVA) antigen-specific T cells, which had been rendered incapable of responding to TGFbeta through T-cell-specific transgenic expression of a dominant-negative variant of the TGFbeta receptor II (dnTGFRII), was analyzed after adoptive transfer into prostate OVA-expressing transgenic (POET) mice. The role of TGFbeta signaling in endogenous T cells in mice, which spontaneously form tumors, was also assessed by monitoring prostate tumor formation and progression in F1 progeny of productive matings between transgenic adenocarcinoma of the mouse prostate (TRAMP) and dnTGFRII mice. TGFbeta-resistant CD8(+) T cells proliferated more and produced IFNgamma more readily after OVA stimulation in vitro. OVA-specific T cells did not damage the prostate gland of POET mice irrespective of TGFbeta responsiveness. However, ex vivo activation facilitated entry of TGFbeta-insensitive T cells into the prostate and was associated with prostate tissue damage. Early tumor progression was delayed in TRAMP mice that carried endogenous TGFbeta-insensitive T cells. Together, these results suggest that TGFbeta-signaling represses CD8(+) T-cell responses to a prostate-specific antigen. TGFbeta-mediated repression of T-cell function may include production of IFNgamma, which is known to contribute to tumor immunosurveillance.
Diener
Kerrilyn R
KR
Experimental Therapeutics Laboratory, Hanson Institute, Adelaide, SA, Australia.
Woods
Anthony E
AE
Manavis
Jim
J
Brown
Michael P
MP
Hayball
John D
JD
D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology; D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D007124:Immunoenzyme Techniques; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017430:Prostate-Specific Antigen / Q000276:immunology*; D019048:Prostatic Intraepithelial Neoplasia / Q000276:immunology* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000276:immunology*
D016212:Transforming Growth Factor beta; D017430:Prostate-Specific Antigen