Chairman, Immunology Program; Director, Ludwig Center of Cancer Immunotherapy; David H. Koch Chair in Immunologic Studies; Attending Immunologist, Department of Medicine; Investigator, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center
Research Interests
The general area of our research is the molecular immunology of the T cell antigen receptor complex, co-stimulatory receptors, and other molecules involved in T cell activation. We are particularly interested in defining those signaling events that lead to differentiation of naive T cells and those that determine whether antigen receptor engagement will lead to functional activation or inactivation of T cells. The lessons learned in these basic studies are used to develop new strategies for the treatment of autoimmune diseases and for immunotherapy of cancer.
Current Projects
T lymphocytes play a major role in the immune response, performing both direct effector and indirect regulatory roles. T cells develop in the thymus, where gene segments recombine to generate diverse antigen receptors (TCR), and selective processes occur that give rise to a functional repertoire capable of recognizing foreign antigens in the context of self major histocompatibility antigens. We are examining the molecules and processes involved in the differentiation and activation of T cells in the mouse.
One of our major areas of current interest is in the mechanisms that regulate T cell responses and the development of strategies for manipulating the process in clinical situations, such as autoimmunity, allergy, vaccination, and tumor therapy. It is now well accepted that recognition of specific antigen by the TCR is not sufficient for activation but that a second antigen nonspecific "co-stimulatory" signal is required. We have demonstrated that this second signal is provided the co-stimulatory receptor CD28 upon recognition of its counter-receptors, members of the B7 family, on the antigen-presenting cell. CD28 engagement is required under most situations for IL-2 production and proliferation. The lack of a CD28-mediated co-stimulatory signal upon TCR engagement can result in the induction of a long-lived state of nonresponsiveness. We are studying the intracellular mechanisms of co-stimulatory signal transduction. We are also examining the relevance of this costimulatory model of T cell activation to immune responses in vivo with the goal of understanding the basis of self-tolerance and to develop means for regulating immune responses.
We have recently found that co-stimulation is more complex than previously thought. CTLA-4, a homolog of CD28, also binds members of the B7 family, and binds them with affinities much higher than CD28. A wealth of data accumulated in the past few years show that CTLA-4 is an important downregulator of T cell responses. We have proposed that CTLA-4 plays a critical role in both the initiation and termination of T cell responses. According to this view, T cell activation is a dynamic process that is determined by the strength of the TCR signal; the strength of co-stimulation provided by CD28; and the magnitude of inhibitory signals generated by CTLA-4. We have begun to analyze the mechanisms by which the signals generated by these different pathways are integrated in T cell activation. We have found that CTLA-4 and CD28 have distinct sites of localization in the T cell, and that both transit to the site of T cell receptor engagement upon the encounter of the T cell with an antigen presenting cell. We are currently studying this relocalization in the context of formation of the immunological synapse between the T cell and the APC.
We have also shown that blockade of CTLA-4in vivo by administration of anti-CTLA-4 antibodies to tumor-bearing mice can greatly enhance anti-tumor T cell responses. In some cases, we have obtained rejection of even well established tumors. We have also demonstrated that CTLA-4 blockade can be used in combination with other methods of immunopotentiation or even conventional chemotherapy to obtain rejection of resistant tumors. We are currently examining the cellular and molecular mechanisms of the anti-tumor effect. The strategies we have developed in the mouse are currently in clinical trials for evaluation of effectiveness in treatment of prostate cancer and melanoma.
