The goal of this laboratory is to understand how T cells respond to self-antigens in the context of tumor immunity and autoimmune disease. As they mature in the thymus, most high avidity self-reactive T cells are deleted, although a small fraction escape negative selection and emigrate to the periphery. These residual cells remain tolerant of self-antigen in the absence of abnormal stimuli. However, under certain circumstances, they may become activated to cause pathologic responses. By understanding how T cells become activated and what regulates their tolerant state, we plan to utilize this knowledge to elicit potent anti-tumor responses and to define novel approaches to treating autoimmune disease.There are 3 on-going projects in this laboratory. The first project is a melanoma-related project that is examining tolerance to a pigmentation antigen, TRP-2, which is co-expressed by both melanoma cells as well as their non-transformed counterparts, melanocytes. In this model system, we reported that sensitization to TRP-2 can elicit autoimmunity (which manifests as depigmentation of the hair) in the absence of tumor immunity and that provision of the cytokine GM-CSF can convert the autoimmune response into an anti-tumor immune response. This apparent induction of tumor immunity is due to an increase in tumor antigen-specific T cells as well as a concomitant increase in dendritic cells. On-going studies are determining the phenotype and functionality of these recruited dendritic cells. In addition, in collaboration with Lionel Feigenbaum, Nick Restifo, and Enzo Bronte, we are generating transgenic mice that bear rearranged T cell antigen receptors (TcRs) specific for TRP-2. We will use anti-TRP-2 TcR transgenes of different affinity and TRP-2-deficient mice to study how TcR affinity influences tolerance and tumor immunity. The second project involves studying T cell reactivity to tumor antigens using a murine model of prostate cancer. In the 'TRAMP' model, mice develop primary prostatic tumors as a result of transgenic expression of the SV40 T antigen (TAg) under the control of a prostate-specific promoter. In our studies, TRAMP mice are adoptively transferred with T cells derived from TcR transgenic mice that have specificity for either a class I- or class II-restricted epitope of TAg. In studies being prepared for publication, we have observed that transfer of the class I-restricted T cells into TRAMP mice results in an initial proliferative expansion followed by deletion from the peripheral lymphoid organs, but retention in the prostate, the site of tumor formation and are unresponsive to antigenic stimulation unless IL-2 is provided. However, vaccination of mice with a dendritic cell vaccine causes an increase in the accumulation of T cells in the prostate and retention of reactivity, associated with a decrease in prostate weight. We are now studying the influence of T antigen-specific CD4+ T cells on CTL responses. On-going studies are determining gene expression profiles of T cells following anergy induction as well as characterization of signals that recruit T cells to the prostate. Finally, we are following up on the observation that Tag-specific T cells from TRAMP mice may function as regulatory or suppressor T cells.Our third project is studying the effects of IL-2 family cytokines on regulatory T cell function. In collaboration with Scott Durum and Protul Shrikant, we have observed that Treg function is induced by TcR ligation in association with provision of IL-2, but not IL-7 or IL-15. Interestingly, IL-21 seems to have a weak but detectable effect on Treg function. Similarly, exposure to an exogenous source of IL-2 (and to a lesser extent IL-21, but not IL-7 or 15), in the presence of Tregs, reverses the suppressive activity. These findings have critical relevance to cancer immunotherapy, where these cytokines are often used as adjuvant therapies.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010563-02
Application #
7291876
Study Section
(LMI)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Zhu, Ziqiang; Cuss, Steven M; Singh, Vinod et al. (2015) CD4+ T Cell Help Selectively Enhances High-Avidity Tumor Antigen-Specific CD8+ T Cells. J Immunol 195:3482-9
Singh, Vinod; Ji, Qingyong; Feigenbaum, Lionel et al. (2009) Melanoma progression despite infiltration by in vivo-primed TRP-2-specific T cells. J Immunother 32:129-39
Shafer-Weaver, Kimberly A; Watkins, Stephanie K; Anderson, Michael J et al. (2009) Immunity to murine prostatic tumors: continuous provision of T-cell help prevents CD8 T-cell tolerance and activates tumor-infiltrating dendritic cells. Cancer Res 69:6256-64
Chen, Xin; Murakami, Takaya; Oppenheim, Joost J et al. (2005) Triptolide, a constituent of immunosuppressive Chinese herbal medicine, is a potent suppressor of dendritic-cell maturation and trafficking. Blood 106:2409-16
Roden, Anja C; Moser, Michael T; Tri, Samuel D et al. (2004) Augmentation of T cell levels and responses induced by androgen deprivation. J Immunol 173:6098-108
Hurwitz, Arthur A; Ji, Qingyong (2004) Autoimmune depigmentation following sensitization to melanoma antigens. Methods Mol Med 102:421-7