Research in the Butcher Laboratory
Eugene Butcher's research focuses on the development and trafficking of cells of the immune system. He discovered the tissue-specificity of lymphocyte-endothelial recognition, which targets immune responses and immune surveillance, and with Irv Weissman identified the first lymphocyte homing receptor, L-selectin (CD62L). His group generated monoclonal antibodies and applied genetic approaches to identify and characterize adhesion and chemoattractant receptors that target lymphocytes (and other leukocytes) to lymphoid tissues, skin, intestines, and other tissues. The laboratory also discovered tissue-specific vascular adhesion receptors ("addressins") that control lymphocyte homing, as well as vascular adhesion receptors for monocytes; and proposed and validated the multistep paradigm of leukocyte and lymphocyte recruitment. This required development of methods to study the molecular contribution of selectin and integrin adhesion receptors and of chemokines in lymphocyte-HEV interactions using in situ videomicroscopy. They also applied in vitroadhesion assays in pioneering studies of the role of chemokines in lymphocyte 'arrest' under flow, and in analyses of the signaling mechanisms involved.
In recent studies, the laboratory has discovered that plasmacytoid dendritic cells home to the thymus, transporting peripheral antigens to the thymus where they induce central tolerance. Using novel genetic and cellular approaches, the group is investigating the role of DC trafficking and antigen transport for systemic tolerance to oral antigens and gut flora; and the importance of DC trafficking to immune homeostasis vs autoimmunity.
The Butcher group is also exploring mechanisms that imprint immune cell (lymphocyte and dendritic cell) homing and chemokine receptor expression for tissue-specific immune responses, and is developing techniques to recapitulate such regulation in vitro for cell targeting and therapy. Dendritic cells (DC) play an important role in the context of T cell programming, and the group is investigating the mechanisms by which specialized DC "interpret" and process local environmental signals (e.g. vitamins, metabolites, cytokines) to control T cell trafficking and regulatory vs. effector activities. For example, the group discovered a role for Vitamin D, produced by sunlight in the skin, in DC programing of T cell epidermotropism (skin homing). In other studies the lab has discovered that environmental factors (e.g. wnt proteins, retinoic acid, other metabolites) control DC precursor development (in the bone marrow) and DC specialization within target tissues as well, with consequences for immune tolerance and inflammation.
In other studies the group is investigating the specialization of the vascular endothelium. Questions focus on the regulation of vascular addressins and inflammatory phenotypes involved in immune cell recruitment. In vitro models, bioinformatic approaches, and in situ visualization and genetic approaches using endothelial-specific inhibition or activation of candidate signaling pathways, are being applied to dissect the molecular and genetic mechanisms involved.
In addition, the Butcher laboratory maintains an interest in therapeutic manipulation of immune cell trafficking, for example in models of colitis, multiple sclerosis, atherosclerosis and psoriasis. Targets and insights from the lab's research have led to clinical stage antibody and small molecule therapeutics for inflammatory bowel disease.