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Andrew C. Chan Senior Vice President: Immunology and Antibody Engineering |
"My laboratory is interested in the molecular mechanisms that regulate immune cell fate. Over the past years, we have focused on four major biological topics:
1. Regulation of T cell function by the PEP (PTPN22) protein tyrosine phosphatase (PTPase). These studies have revealed a selective regulation of effector T cell function by this PTPase. Mice deficient in PEP demonstrate normal naïve T cell function, but hyperactive effector T cell antigen receptor (TCR)-mediated cytokine production and proliferation. Moreover, these mice develop spontaneous germinal centers but do not develop autoimmune disorders. These studies demonstrate that expansion of effector cells and formation of spontaneous germinal centers are not sufficient to induce autoimmune disorders. We are presently continuing to study why PEP selectively regulates effector T cell functions as well as additional signals required for the generation of autoimmunity. (Hasegawa, et al, Science, 303:685-689, 2004)
2. Cytoskeletal reorganization and lymphocyte survival. We have recently demonstrated a dynamic relationship between F-actin formation and lymphocyte homeostatic mechanisms. Mice deficient in a negative regulator of F-actin formation (coronin 1) demonstrate enhanced basal levels of F-actin and surprisingly decreased lymphocyte survival. Coronin 1-deficient T cells demonstrate enhanced caspase activation and increased mitochondrial permeability that result in T cell apoptosis. As increased F-actin levels are associated with increasing age, we are investigating the relationship of how cytoskeletal disorganization may affect immune dysfunction. (Foger, et al, Science 313:839-842, 2006)
3. Subcellular localization of signal transduction events. While most signal transduction studies have focused on transmembrane signaling, we are studying the importance of signals that emanate not at the cytoplasmic membrane surface, but within the endosomal compartment. While Fas ligand binds transmembrane Fas receptor (FasR), our studies reveal an additional signaling function of the FasR that occurs within the intracellular endosomal compartment. Inhibition of FasR internalization inhibits association of FADD with activated FasR, caspase activation and cellular apoptosis. Moreover, inhibition of FasR internalization not only results in inhibition of death signals, but permits engagement of the FasR to activate pro-survival pathways through activation of NFkB and Erk signaling pathways. Hence, the subcellular localization of signaling plays a critical role in defining receptor-mediated cellular fates. (Lee, et al, EMBO J, 25:1009-1023, 2006)
4. B cell immunotherapy. We are investigating the in vivo mechanisms that govern antibody-mediated depletion of immune cells. The generation of a murine model in which anti-human CD20 mAbs (e.g., Rituxan) have permitted us to understand factors governing B cell depletion by therapeutic mAbs. We are utilizing these and other models to develop additional novel immunotherapies for the treatment of hematopoietic cancers and autoimmune disorders. (Martin & Chan, Annu Rev Immunol 24:467-496, 2006; Gong, et al, J Immunol 174:817-826, 2005; Martin & Chan, Immunity, 20: 517, 2004)"