|
|
||||||
| Molecular mechanisms of lymphocyte activation in normal immunity, autoimmunity, and malignancy | |||||||
| The Bishop lab studies molecular mechanisms of lymphocyte activation. By working to understand how cells communicate with one another and their environment, we address questions of how normal immunity, autoimmunity and malignancy are regulated. A major focus of our work is understanding signals delivered to cells by members of the Tumor Necrosis Factor Receptor (TNFR) superfamily of molecules. This large family of receptors is expressed on many cell types, but is of special importance to regulating the activities of cells of the immune system. One of the family members that we study, CD40, is expressed primarily on immune cells that present antigen to T lymphocytes, including B lymphocytes, the immune cells that produce antibodies. CD40 plays a critical role in B cell function. In parallel, we study a protein produced by Epstein-Barr virus, called latent membrane protein 1 (LMP1), which plays important roles in the development of EBV-associated lymphomas that can arise in immunosuppressed patients, and also contributes to disease flares in Lupus and arthritis. LMP1 is a remarkable mimic of CD40 signals, but in an amplified and dysregulated manner. Using combined approaches of cell line studies, freshly isolated cells (mouse and human) and genetically altered mice, we are investigating how signaling by CD40 and LMP1 differ. A key difference is how the two receptors regulate the function of a family of cytoplasmic proteins called TNFR associated factors (TRAFs). We are also studying how TRAF function and regulation contributes to cell signaling by TNFR family members, including CD95, TNFR2, CD27, BAFFR and TACI, as well as the innate immune TLR receptors. Some of the molecules we have begun to study regulate T cell activating and apoptotic signals delivered by the T cell antigen receptor. We have developed a method using gene targeting by homologous recombination in somatic cells to produce cell lines specifically and completely deficient in single of multiple types of TRAF molecules, as well as mice that lack particular TRAFs in certain cell types. Another line of investigation in the lab involves understanding how innate immune receptor signals interact with signals via adaptive receptors, such as antigen receptors. We are examining such signals and their roles in optimizing the use of B lymphocytes in cellular vaccines to protect from infectious organisms and malignant cells. | |||||||
| Selected Publications | |||||||
| Click Here for a Complete List of Articles | |||||||
|
Kraus, Z.J., Haring, J.S., and Bishop G.A. TRAF5 is required for optimal T cell expansion and survival in response to infection. J. Immunol. 181:7800-7809, 2008.
Graham, J.P., Moore, C.R. and Bishop G.A. Roles of the TRAF2/3 binding site in differential B cell signaling by CD40 and its viral oncogenic mimic, LMP1. In press, J. Immunol., 2009. Poovassery, J.S., Vanden Bush, T.J., and Bishop G.A. Antigen receptor signals rescue B cells from TLR tolerance. In press, J. Immunol., 2009. Kraus, Z.J., Nakano, H. and Bishop G.A. TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40. Proc. Natl. Acad. Sci. (USA), In press 2009. VandenBush, T.J., Buchta, C.M., Claudio, J. and Bishop G.A. Cutting Edge: Importance of IL-6 and cooperation between innate and adaptive immune receptors in cellular vaccination with B lymphocytes. In press, J. Immunol., 2009. |
|||||||
| Department/Program Affiliations |
| Microbiology |
| Biosciences |
| Immunology |
| Internal Medicine |
| Molecular and Cellular Biology |
| MSTP |