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. This year, in collaboration with Lionel Feigenbaum, Nick Restifo, and Enzo Bronte, we have generated transgenic mice that bear rearranged T cell antigen receptors (TcRs) specific for TRP-2. We have observed that T cells from these TcR transgenic mice maintain repsonsiveness to their cognate antigen despite peripheral expression of the antigen. We are now characterizing TcR trangenic mice that bear transgenes encoding TcR of differing affinities.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 submitted 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 have observed that Tag-specific T cells from TRAMP mice function as regulatory or suppressor T cells. This latter work is being preapred for publication.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, despite expression of its receptor, IL-21 seems to have a minimal effect on Treg function. Similarly, exposure to an exogenous source of IL-2 (but not IL-21, IL-7 or 15), in the presence of Tregs, reverses the suppressive activity.
