Role of T Cell-Microglial Cell Interaction in Tissue Damage in the CNS

Michael L. Dustin, Ph.D.

Skirball Institute, New York University

Grant Program:

Neuroimmunology

Funded in:

March 2003, for 3 years

Funding Amount:

$300,000

Abstract

Role of T Cell-Microglial Cell Interaction in Tissue Damage in the CNS

The role of microglial cells' activation and T cell interactions with microglial cells in remodeling neural connections in response to tissue damage is not known. Autoimmune conditions and infectious processes can cause significant behavioral and motor function changes, suggesting that destruction or remodeling of neural connections is a characteristic of these processes. Recently, we have used intravital two-photon laser scanning imaging in the adult mouse brain to directly quantify neural connections in the visual cortex. It was found that these connections are stable over a period of months. This stability provides an outstanding baseline for assessing the association of microglial cell dynamics with changes in synaptic connections in the adult brain at sites of acute tissue damage and for determining the role of immunologically specific interactions with T cells in the regulation of these neural changes.

In the first aim, we will examine the acute and long term effects of very specific laser-induced damage on microglial cell motility and changes to surrounding synaptic connections. We will then perform similar experiments in which damage is induced by microinjection with a fine needle and antigen to induce the interaction of antigen specific effector T cells with microglial cells. The fundamental variable of an immune stimulus, antigen and adjuvant, will be systematically varied. Imaging in live animals is essential for these experiments, because outcomes are measured in terms of the loss of synaptic connections, which can be visualized at different distances from a lesion and at different times in the same animal. These results will provide insights into the roles of immunological activation in neural damage at a highly quantitative level.

Investigator Biographies

Michael L. Dustin, Ph.D.

Dr. Michael Dustin is the Irene Diamond Professor of Immunology of the Skirball Research Institute at the New York University School of Medicine. He received his Ph.D. degree from Harvard University in 1990. His laboratory focuses on understanding fundamental aspects of T cell activation, including the formation and signaling of the immunological synapses between T cells and antigen presenting cells and the interactions and trafficking of immune cells in the living mice with intravital imaging methods. Dr. Wenbiao Gan is an associate professor in the Department of Physiology and Neuroscience and a member of the Skirball Research Institute at the New York University School of Medicine. He received his Ph.D. degree from Columbia University in 1995. His laboratory focuses on understanding structural plasticity and pathology of synapses in the cerebral cortex, as well as the function of microglia in normal and pathological brain.

Selected Publications

Haynes S.E., Hollopeter G., Yang G., Kurpius D., Dailey M.E., Gan W.B., and Julius D. The P2Y(12) receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci. 2006 Dec;9(12):1512-9.

Kim J.V. and Dustin M.L. Innate response to focal necrotic injury inside the blood-brain barrier. J Immunol. 2006 Oct 15;177(8):5269-77.

Davalos D., Grutzendler J., Yang G., Kim J.V., Zuo Y., Jung S., Littman D.R., Dustin M.L., and Gan W.B. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005 Jun;8(6):752-8.