My lab focuses on the study of human ?? T cells and nonpeptide antigens. T cells are a distinct subset of T cells that function to bridge innate and adaptive immunity by recognizing nonpeptide, isoprenoid metabolites and by performing unique roles not played by ?? T cells. ?? T cells are very important in human microbial immunity as evidenced by the large expansions of V?2V?2 T cells (up to 1 in 2 circulating T cells) that occur during many bacterial and parasitic infections. Moreover, once activated, V?2V?2 T cells kill most types of tumors by recognizing them using the NK receptors that they express. Thus, efforts are ongoing to determine how to use V?2V?2 T cells for cancer immunotherapy

We have found that human ?? T cells use their V?2V?2 antigen receptors to recognize essential phosphorylated metabolites in isoprenoid biosynthesis. Bacteria and protozoan parasites use a different metabolic pathway to make isoprenoids than humans which use the mevalonate pathway. V?2V?2 T cells recognize one of the intermediates in this pathway, termed HMBPP. They also recognize the self-metabolite, IPP, which accumulates in cells after aminobisphosphonate drug treatment. One area of focus of the lab is to determine how these small phosphoantigens are presented to V?2V?2 T cells by identifying its novel antigen presenting molecule. We are also working to identify a novel bacterial antigen produced by Staphylococcus aureus and other Gram-positive cocci despite their use of the mevalonate pathway, the biochemical pathway responsible for its synthesis, and to determine the role of V?2V?2 T cells in immunity to Gram-positive cocci.

A second area of study has focused on the development of memory in ?? T cells. We have found that distinct memory subsets of V?2V?2 T cells exist. These V?2V?2 subsets have different migratory and functional abilities. The different migration is due to differential expression of adhesion molecules and chemokine receptors that determine the homing capabilities of cells. Our present studies focus on the factors that control the generation of memory V?2V?2 T cells and the relative importance of the different memory subsets in bacterial and tumor immunity. We are also studying IL-17A and IL-22 production by V?2V?2 T cells to determine the cytokines and signals controlling their differentiation into Th17-like cells and their functional significance in human microbial immunity and autoimmunity.

A third area of study is to develop ?? vaccines for bacterial infections and for cancer immunotherapy. In clinical trials, stimulating V?2V?2 T cells has resulted in partial and complete remissions in some cancer patients with lymphoma, prostate cancer, and renal cell carcinoma. We are engineering the metabolism of vaccine bacteria to make them overproduce the HMBPP antigen as vaccines for ?? T cells. We are also studying new lipophilic bisphosphonates. In preclinical studies, we are testing these vaccines in monkeys and in immunodeficient mice transplanted with human blood cells.