B.S., Butler University, 1988
Ph.D., Washington University, 1993
phone: (336) 716-5936
"My job as a mentor is to help my students reach their potential as scientists. Achievement of this goal requires the development of a relationship that fosters an environment in which students feel they can freely express their ideas. The learning process is guided by me, but the goal is for the student to be able to think in an increasingly independent fashion with regard to the direction the project should take and the next experiment that should be performed."
Regulation of CD8+ T cell avidity. My laboratory is interested in understanding the activation and regulation of CD8+ cytolytic T lymphocytes during the course of viral infections. A number of molecules and environmental influences are known to be involved in the activation of these cells; however, many aspects of precisely how these interactions contribute to the regulation and resulting functional phenotype of CTL are unknown. The repertoire of CTL specific for a particular peptide antigen can encompass a broad range of sensitivities to peptide antigen, termed functional avidity. In recent work using a TCR transgenic model system, we have found that avidity can be modulated by the altering the isoform of CD8 expressed (aa homodimers versus aß heterodimers). Expression of the aß heterodimeric form of CD8 promotes co-localization of CD8 with the TCR facilitating optimal TCR signaling and thus activation. Current studies focus on understanding the control of CD8 expression and the effect of CD8 on the formation of the immunological synapse. In addition, recent studies have begun to analyze the TCR signal transduction pathway in cells of high versus low avidity. In most cases the level of peptide presented by an antigen presenting cells determines the avidity of the CTL. However, recently we made the surprising discovery that mature dendritic cells generate high avidity cells regardless of the level of presented peptide. This suggests that the signals resulting from the interaction of dendritic cells and naïve T cells is fundamentally different than those generated as a result if interaction with other APC. Defining these differences is an area of active investigation in the lab.
My laboratory is also studying the regulation of high versus low avidity CD8+ T cells generated following respiratory infection. We have found that there is a kinetic separation in the activation/expansion of high and low avidity cells with high avidity cells selectively elicited early following infection. As high avidity cells are known to be a critical component of an optimal anti-viral response, current studies are aimed at identifying the mechanisms responsible for selective activation of high avidity cells as the initial population of responding cells. Information gained may lead to the design of improved vaccines that will be optimal for elicitation of high avidity cells.
DC maturation following respiratory infection. A second area of active investigation is the regulation of dendritic cell (DC) maturation. DC are the most potent activators of naïve T cells and thus play a critical role in the generation of an anti-viral response. For these studies we utilize two viral model systems, the paramyxovirus SV5 and the poxvirus Vaccinia virus. We have found that DC maturation in vivo in the context of infection does not reflect what occurs in vitro. Understanding how DC are regulated following infection in vivo and the resulting effect on the generation of a CTL response is likely to provide important insights into the design of more effective vaccines.
Regulation of CTL function in the lung. Recruitment of CTL to the lung is critical for clearance of many respiratory viral infections. Our studies have revealed that the lung environment is capable of inducing loss of function in CTL entering this tissue. This is a novel finding and suggests that mediators present in this tissue have the capability to profoundly regulate the immune response. Current studies are focused on determining the mediator responsible for “turning off” T cells in this tissue, focusing on the cell type capable of mediating this effect. We are also actively assessing signaling in the non-functional cells to determine the defect in the transduction pathway.