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 publications, contact information, other information Research Interests My laboratory is interested in the regulation of T lymphocyte activation and differentiation. T cell activation requires a complex set of cellular and molecular interactions centered on the specific interaction between the T cell antigen receptor (TCR) and antigen displayed by antigen presenting cells. Following recognition of antigen, the T cell receptor complex initiates a cascade of signal transduction pathways which can lead to a wide variety of different (although sometimes overlapping) outcomes including proliferation, distinct patterns of cytokine production, apoptosis and anergy. The regulation and identification of the signaling mechanisms responsible for producing these different outcomes are not well understood. Over the past several years my research has focused on the macromolecular organization of the T cell receptor complex and associated molecules and how alterations in the T cell receptor signaling complex can affect early biochemical signaling events as well as downstream events such as cytokine production. Below is a list of three projects which address this issue. 1. CD45 regulation of T cell activation. CD45 is the predominant transmembrane tyrosine phosphatase in lymphocytes and is required for T cell activation. We have found that CD45 association with the T cell receptor complex can regulate T cell signaling and cytokine production and are currently studying the mechanisms by which CD45 association with the T cell receptor is regulated following T cell activation and differentiation. 2. CD4 regulation of T cell activation. CD4 can serve as a coreceptor for the TCR and can modulate T cell activation by facilitating interaction with antigen and antigen presenting cells, and because of an association with the src family kinase, lck which helps to initiate the TCR signaling cascade. More recently we have found that CD4 is required for the differentiation of T cells into IL-4 secreting effector cells. The molecular mechanism for CD4 regulation of T cell differentiation is being investigated. 3. Changes in the macromolecular T cell receptor complex during differentiation. Following antigen recognition T cells can differentiate into specialized effector cell subsets (referred to as Th1 and Th2 cells) able to produce distinct patterns of cytokines. The T cell receptor signaling complex in these cell subsets is pre-configured to respond to antigen in a subset specific manner. This project aims to understand the molecular basis for these differences and to develop novel approaches to specifically regulate these T cell subsets. Selected Publications Top 1. Leitenberg, D., Y. Boutin, S. Constant, and K. Bottomly. 1998. CD4 regulation of T cell receptor signaling and T cell differentiation following stimulation with peptides of different affinities for the T cell receptor. J. Immunol. 161: 1194-1203. 2. Leitenberg, D., Y. Boutin, D. Lu, and K. Bottomly. 1999. Specific biochemical association of CD45 with the T cell receptor: regulation by CD45 isoform and during T cell activation. Immunity. 10:701-711. 3. Leitenberg, D. and K. Bottomly. 1999. Regulation of naïve T cell differentiation by varying the potency of TCR signal transduction. Seminars in Immunology. 11:283-292. 4. Leitenberg, D., F. Balamuth, and K. Bottomly. 2001. Differential regulation of the T cell receptor macromolecular complex and recruitment into raft microdomains during Th1 and Th2 differentiation. Seminars in Immunology. 13:129-38 5. Balamuth, F., D. Leitenberg, J. Unternaehrer, I. Mellman, and K. Bottomly. 2001. Distinct patterns of membrane microdomain partitioning in Th1 and Th2 cells. Immunity;15:729-38. Contact Information Top David Leitenberg, M.D., Ph.D. Ross Hall, Room 411 Phone: (202) 994-9475
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