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Postdocs
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Maureen McGargill, Ph.D. I am studying the role of DRAK2 in T cell development, signaling, and function. DRAK2 is a member of the DAP kinase family. This is a novel subfamily of serine/threonine kinases, which are capable of inducing apoptosis in a variety of cells. DRAK2 is expressed highest in the lymphoid tissues, including spleen, thymus, and lymph nodes. In the thymus, expression levels change as the thymocyte proceeds through development. To investigate the role of this kinase in T cell development and function, we created DRAK2 deficient mice. Interestingly, there was no defect in apoptosis induced by various agents in either thymocytes or peripheral T cells. In addition, negative selection was unaffected in two in vivo models. However, to our surprise, there was an increase in positive selection of DRAK2 deficient T cells. These T cells fluxed increased levels of calcium, produced more IL-2, and proliferated to a greater extent in response to antigen than wildtype T cells. In addition, in the absence of DRAK2, T cells required less co-stimulation for antigen-induced proliferation than wildtype T cells. Furthermore, the response to an in vivo viral infection was altered in that the peak and the contraction of the response was earlier than in wildtype mice, and more antigen-specific T cells remained following the contraction. These data imply that DRAK2 negatively regulates TCR-induced signals. I am currently investigating the biochemical mechanism in which DRAK2 suppresses signals originating from the TCR, and further if the removal of this suppression results in an increased propensity to autoimmune disease. | |
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Warren D'Souza, Ph.D. Some extremely important issues facing immunologists today concern the factors that regulate T cell proliferation, differentiation, and survival following their activation by pathogens. As of now, little is known in this regard and one of my projects aims at trying to understand some of the parameters that govern the burst size of an antigen-specific CD8 T cell population and subsequent memory generation. I am using adoptive transfers and MHC class I tetramers along with pathogens like vesicular stomatitis virus (VSV) and Listeria monocytogenes to track the responding cell populations in vivo and determine the fate of late-recruited cells during an immune response. As mentioned above, our knowledge of the cellular processes that regulate T cell responses in vivo is scarce and we know even less about the molecular mechanisms that govern these processes. In developing invertebrates and vertebrates, the ERK MAP kinase signaling cascade is crucial for the transduction of signals leading to a plethora of cellular responses that include growth, survival, apoptosis and differentiation. Our lab has generated mice that are deficient in ERK2 specifically within T cells and we are using these mice along with ERK1 deficient mice and mice expressing a hypersensitive form of ERK2 (ERK-SM), to comprehensively analyze the functions for ERK1 and ERK2 within CD8 T cells. In particular, the role for ERK1/2 in CD8 T cell homeostasis, activation, proliferation and differentiation in vivo is being examined. |
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Manqing Li, Ph.D. I am working on several projects right now. My first project focuses on the study of the functions of Erk1/2 signaling in the immune system development and differentiation using the Erk1-/-Erk2ASKA/ASKA mouse developed in this lab. ASKA stands for ATP-analog Sensitive Kinase Allele. The mutant kinase has a bigger ATP-binding cavity, which renders it susceptibility to the bulky ATP-analog kinase inhibitor. In the absence of the inhibitor, the ASKA mutant Erk2 behaves like the wild type Erk2. However, the adding of the ATP-analog inhibitor can inhibit the kinase activity of the Erk2ASKA mutant strongly while not affecting the wild type Erk2. Currently, we are interested in using the Erk2ASKA system to identify the functions of Erk1/2 signaling in the development and differentiation of T lymphocyte progenitors and in the lineage commitment of CD4/CD8 SP T lymphocytes. My second project involves using the conditional Erk2 knockout mice to study the functions of Erk1/2 signaling in the mitosis and apoptosis of mouse embryonic fibroblast cells (MEFs). It has been reported that Erk1/2 signaling is important for the G1 to S phase transition in fibroblasts. Our preliminary data suggest that in the complete absence of Erk1/2 signaling, MEFs are still able to divide and proliferate, although at a much lower speed. Further investigation is needed to clarify the exact roles of Erk1/2 signaling in the mitosis and apoptosis of primary cells. I am also working on a project trying to identify a potential novel substrate of the serine-threonine kinase Raf-1 in lymphocytes. |
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Daniel Beisner, Ph.D. Exquisite regulation of lymphocyte cell number, both by cell death and by proliferation, is required to maintain a balance between the generation of a strong adaptive immune response and the development of autoimmunity. Death receptors (DRs) are one way through which cell death can be initiated and their ligation ultimately leads to the activation of a set of aspartic acid proteases, termed caspases, which are responsible for the execution of apoptosis. Fas-associated death domain (FADD) is an adaptor protein that links DRs to the activation of caspases and more specifically Caspase-8. Previous work has shown that DR-induced apoptosis in T cells is effectively abrogated in mice expressing a dominant negative form of FADD (FADDdd). Surprisingly, defects in T cell proliferation were also observed, despite normal early activation events including cytokine production. Further work has shown that FADDdd expressing T cells undergo cell death instead of cell division after activation by antigen receptor. Additionally, FADDdd T cells fail to mount an effective response to lymphocyte choriomeningitis virus infection, demonstrating a requirement for FADD in immune responses in vivo. To determine if B cell proliferation demonstrates a similar requirement for DR signaling, mice with a B cell specific deletion of Caspase-8 were generated. Surprisingly, B cell proliferation induced by antigen receptor was unperturbed in Caspase-8 deficient B cells. However, Caspase-8 deficient B cells failed to survive and proliferate in response to dsRNA and LPS. Signal transduction pathways common to the receptors for these ligands appeared to be intact, including the activation of NF-(B and IRF3. Taken together, these data suggest roles for DR signaling in both lymphocyte cell death and surprisingly, in lymphocyte expansion. It seems T and B cells have developed control mechanisms that limit the expansion of cells that have impairments in the ability to die by DRs. This control mechanism seems appropriate, in that unrestricted cell growth could easily lead to autoimmunity and even cancer. How Caspase-8 and FADD are involved in lymphocyte proliferation and survival, and the differences between T and B cells in their requirements for DR signaling, are the focus of our ongoing research. |
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Division of Biology
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