publications, contact information

Research Interests

Cells of all species have developed evolutionarily conserved, innate responses to exogenous stressors, regulating growth and survival via changes in signal transduction and gene expression. It has become clear that, in response to stimulation of cell surface receptors by agents as diverse as angiotensin II, platelet derived growth factor (PDGF), shear stress or LDL, cells also endogenously generate intracellular oxidative stress to regulate growth and survival.

The major focus of my lab is to investigate the mechanisms by which reactive oxygen or nitrogen species affect the immune system. Our results clearly demonstrate that endogenous reactive species are produced upon T cell receptor (TcR) or Fas stimulation in cultured and primary T cells. Overexpression of specific antioxidant enzymes (catalase and superoxide dismutase) was used to define the ROS produced upon receptor stimulation and is being used to define their biologic role(s) and the molecular targets of receptor stimulated ROS generation. This production of ROS has been shown to regulate TcR-stimulated signal transduction including activation of MAPK and expression of FasL.

Current studies are using knockout and transgenic mouse models and overexpression of dominant negative and dominant active forms of signaling molecules to define pathways regulating ROS generation. We are combining these approaches with biochemical analysis of protein phosphorylation, protein:protein interaction and oxidative modification of proteins to define the mechanisms by which ROS modulate signal transduction and gene expression. New studies are investigating how viral gene products and exogenous toxicants (including chemotherapeutic agents) alter these redox dependent signaling pathways.

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The Role of Reactive Oxygen Intermediates in TcR-Induced Death of T Cell Blasts and Hybridomas. Williams, M.S. and Henkart, P.A. J. Immunology 157, 2395-2402 (1996).

Nitric Oxide Synthase Plays a Signaling Role in TcR-Triggered Apoptotic Death. Williams, M.S., Noguchi, S., Henkart, P.A. and Osawa, Y. J. Immunology 161, 6526-6531 (1998)

Discrete Generation of Superoxide and Hydrogen Peroxide by T Cell Receptor Stimulation: Selective Regulation of MAPK Activation and FasL Expression. Devadas, S., Zaritskaya, L., Rhee, S.G., Oberley, L., and Williams, M.S. J. Exp. Med. (in press) (2001)

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