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| Human γδ T cell Recognition of Nonpeptide Antigens: Discriminating Friend from Foe through the Recognition of Prenyl Pyrophosphate Metabolites. | |||||||
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The Morita lab focuses on the study of human γδ T cells and nonpeptide antigens. γδ T cells are a distinct subset of T cells that function to bridge innate and adaptive immunity by performing unique roles not played by αβ T cells. Pathogen recognition by γδ T cells is very important in human immunity as evidenced by the large expansions of Vγ2Vδ2 T cells that occur in many bacterial and parasitic infections.
We have found that Vγ2Vδ2 T cells use their T cell antigen receptors to recognize essential phosphorylated nonpeptide prenyl pyrophosphate intermediates in isoprenoid metabolic pathways. Bacteria and protozoan parasites use a distinct metabolic pathway to make isoprenoids. Vγ2Vδ2 T cells recognize one of the intermediates in this pathway, termed HMBPP. They also recognize the self isoprenoid metabolite, IPP. Malignant B cells and other tumor cells can be killed by Vγ2Vδ2 T cells since the tumors can overproduce IPP and also can trigger NK receptors expressed by Vγ2Vδ2 T cells. We are determining the molecular basis for this recognition by identifying the novel antigen presenting molecule, isolating and determining the origin of new bacterial antigens through biochemical, synthetic chemistry, and bacterial genetic approaches, and defining TCR regions required for recognition. A second area of study has focused on the development of memory in γδ T cells. We find that distinct memory subsets of Vγ2Vδ2 T cells exist. These Vγ2Vδ2 subsets have different migratory and functional abilities. These differences are 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 Vγ2Vδ2 T cells and the relative importance of the different memory subsets in bacterial and tumor immunity. A third area of study is to develop nonpeptide antigens that stimulate γδ T cells as vaccines to prevent human infections and to treat cancer. Vγ2Vδ2 T cells can recognize and kill malignant B cells and other tumor cells. In early clinical trials, Vγ2Vδ2 T cells stimulated by nonpeptide antigens provided immunity to B cell malignancies in some patients. We would like to determine what tumor antigens are recognized, the importance of costimulatory NKG2D ligands, and what Vγ2Vδ2 memory subsets are important for tumor immunity. We are studying cellular metabolic pathways to determine mechanisms for the production of cellular antigens for Vγ2Vδ2 T cells. We are testing different prenyl pyrophosphate and bisphosphonate compounds to find new vaccine candidates. In preclinical studies, we are testing different vaccination techniques and adjuvants to stimulate Vγ2Vδ2 T cells in monkeys and in human cells transplanted into SCID-beige mice. |
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| Selected Publications | |||||||
| Click Here for a Complete List of Articles | |||||||
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Sarikonda, G., Wang, H., Puan, K.-J., Liu, X.-H., Lee, H.K., Song, Y., Distefano, M.D., Oldfield, E., Prestwich, G.D. and Morita C.T. Photoaffinity antigens for ©™ T cells. J. Immunol. 181:7738, 2008.
Puan, K.-J., Jin, C., Wang, H., Sarikonda, G., Raker, A.M., Lee, H.K., Samuelson, M.I., Märker-Hermann, E., Pasa-Tolic, L., Kolas-Nieves, E., Giner, J-L., Kuzuyama, T. and Morita C.T. Preferential recognition of a microbial metabolite by human Vγ2Vδ2 T cells. Int. Imm. 19:657, 2007. Morita C.T., Jin, C., Sarikonda, G. and Wang, H. Nonpeptide antigens, presentation mechanisms, and immunological memory of human Vγ2Vδ2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens. Immunol. Rev. 215:59, 2007. Zhang, Y., Song, Y., Yin, F., Broderick, E., Siegel, K., Goddard, A., Nieves, E., Pasa-Tolic, L., Tanaka, Y., Wang, H., Morita C.T. and Oldfield, E. Structural studies of Vγ2Vδ2 T cell phosphoantigens. Chem. Biol. 13:985, 2006. Morita C.T., Li, H., Lamphear, J.G., Rich, R.R., Fraser, J.D., Mariuzza, R.A. and Lee, H.K. Superantigen recognition by γδ T cells: SEA recognition site for human Vγ2 T cell receptors. Immunity 14:331, 2001. Tanaka, Y., Morita C.T., Tanaka, Y., Nieves, E., Brenner, M.B. and Bloom, B.R. Natural and synthetic non-peptide antigens recognized by human γδ T cells. Nature (Lond.) 375:155, 1995. Morita C.T., Beckman, E.M., Bukowski, J.F., Tanaka, Y., Band, H., Bloom, B.R., Golan, D.E. and Brenner, M.B. Direct presentation of nonpeptide prenyl pyrophosphate antigens to human γδ T cells. Immunity 3:495, 1995. |
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| Department/Program Affiliations |
| Internal Medicine |
| Biosciences |
| Immunology |
| Molecular and Cellular Biology |
| MSTP |