Research Interests

Our laboratory investigates the general area of interactions between the immune system and the vascular system. Much of our experimental work is focused on three related topics. First, we analyze the capacities of human endothelial cells to serve as antigen presenting cells (APCs), resulting in the activation of T cells. We analyze these processes using cultured cell populations and in vivo, using immunodeficient mice that have been transplanted with human vessels or vascular cells and lymphocytes and accesoory cells. These studies have led to two general conclusions: (1) that human endothelial cells, which basally express both class I and class II MHC molecules in vivo, selectively trigger responses of circulating memory T cells, and (2) that memory T cells activated by endothelial cells may acquire different properties than those activated by conventional APCs. For example, endothelial cells favor the differentiation of cytolytic T lymphocyte populations that selectively kill endothelial cell targets. We also have developed specific molecular strategies to allow endothelial cells to evade interactions with T cells.

Our second focus is the activation of endothelial cells by T cells and their products (e.g., cytokines). In this area, we have concentrated our studies upon TNF signaling pathways. We are particularly interested in how TNFRs are regulated in their expression and subcellular distributions, and how various signaling complexes are assembled and disassembled within various intracellular compartments. We also study how TNF-induced adhesion molecules are displayed by endothelial cells, and how these molecules may contribute to endothelial cell responses during inflammation beyond their known functions in leukocyte rolling and capture.

The third focus of our laboratory is on endothelial injury and resistance to injury. We are particularly interested in how TNF and IFN-γ may interact to initiate caspase-dependent and cathepsin B-dependent cell death responses, and how these responses may be manipulated by therapies.

The specific research interests of the Pober laboratory have been extended, through collaborations with other Yale scientists in Immunobiology, in the Vascular Biology and Transplantation Program, and in Biomedical Engineering, in order to address broader questions in immunology and vascular biology. For example, our studies of the ability of endothelial cells to activate and drive cytokine production by T cells has led to the discovery of new roles for IFN-γ in arteriosclerosis. The ability of endothelial cells to selectively interact with memory T cells has led to an understanding of how endothelial cells may influence the course of infection of memory T cells with HIV. Finally, the development of strategies that allow endothelial cells to evade immune detection or resist immune-mediated injury has led to applications in cell transplantation and tissue engineering.