SUMMARY OF RESEARCH INTERESTS

Spatiotemporal Control of T cell Interactions

Cell-cell interactions are of central importance in the development and maintenance of multicellular organisms. While the biochemical players for these interactions are known, the dynamics of how any of these molecules work in their natural environment has been technically very difficult to approach. We are addressing these problems using real-time 3D imaging approches. Our research projects are aimed to understand the spatial and temporal dynamics that regulate immune activation versus immune tolerance. Work is focussed in two areas:

• Molecular Coordination in T cell Signaling.
  T cell receptors undergo a coordinated series of clustering events during the onset of signaling resulting in the formation of an 'immunological
  synapse'. Most notably small elementary receptor clusters are coalesced into a single cluster at the center of the T cell/antigen-presenting cell
  interface. Coincident with this, the entire T cell undergoes a repolarization event in which T cell receptors are recruited along the membrane to the interface region. Our recent data suggest that myosin motors are critical for controlling polarization of the TCR toward the APC and, as such, also profoundly affect the duration and magnitude of intracellular signaling. In addition, concerted recruitment of co-receptors and costimultory molecules is involved in generating sustained signaling. Understanding the activities and mechanisms that control events of T cell activation is a outstanding issue in the field of T cell activation.
  
  
• Molecular Coordination in Multipartite Interactions.
  Multiple intercellular contacts give rise to the complex systems behavior of the immune system. We are extending our imaging systems in order to study interactions amongst a variety of T cell partners such as dendritic cells and macrophages. Of particular interest are the multipartite interactions in which three or more cells come together simultaneously or sequentially to
  create complex biology. Novel biological insights can be gleaned by understanding the nature of cooperative and competitive cellular interactions. In addition, we are using molecular genetics coupled with imaging to identify novel molecular players whose localization at the cell-cell contact suggests participation in initiation or maintenance of the interaction. Our ultimate goal is to uncover the methods by which the immune system regulates the decision between tolerance and immunity.