UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

Molecular Coordination in T cell Signaling (TCRs)

T cell receptors (TCRs) 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 TCRs 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 co-stimultory molecules is involved in generating sustained signaling. Understanding the activities and mechanisms that control events of T cell activation is an 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 3 or more cells come together si multaneously 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.

Selected References

Jacobelli, J. Chmura, S.A., Buxton,D.B., Davis , M.M. and Krummel, M. F. 2004. Class II Myosin Heavy Chain 2A/MyH9 Is Involved in the T Cell Stop Signal but is not Required for Synapse Formation. Nature Immunology 5, 531 - 538 .

Jacobelli, J., Andres, P.G., Boisvert, J., and Krummel, M.F. 2004. New Views of the Immunological Synapse: Variations in Assembly and Function. Curr Opin Immunol 16, 345-52.

Boisvert, J., Edmondson, S. and Krummel, M.F. 2004. Immunological Synapse Formation Licenses CD40-CD40L Accumulations at T-APC Contact Sites. J. Immunol. 173, 3647-3652.

Tooley,A.J., Jacobelli, J., Moldovan, M-C., Douglas, A., and Krummel, M.F. 2005. T cell Synapse Assembly: Proteins, Motors and the Underlying Cell Biology. Seminars in Immunology , 17, 65-75.

Website: http://www.ucsf.edu/pathol/krummel/

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