Matthew Krummel, PhD

Spatiotemporal Dynamics of T cell activation in vitro and in vivo

Associate Professor, Department of Pathology
513 Parnassus, HSW 502, Box 0511
San Francisco, CA 94143

(415) 514-3130 tel
Email

Lab website

AA: Christine Lin

Description of Research

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 focused in two areas:

1. 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.

2. T cell activation in vivo
Multiple intercellular contacts give rise to the complex systems behavior of the immune system. We are interested in  imaging and understanding the temporal dynamics ofinteractions amongst a variety of T cell partners such as dendritic cells and macrophages within effector sites. One area of particular interest are the multipartite interactions in which three or more cells come together simultaneously or sequentially to create complex biology--for example when multiple T cells meet up in their activation phases. 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 movement at the cell-cell. Our ultimate goal is to uncover the methods by which the immune system regulates the decision between tolerance and immunity.

1. 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.

2. 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.

3. Okada, T. Miller, M.J., Parker, I., Krummel, M.F., O'Garra,A. Cahalan,M.D., Cyster, J.G. 2005. Antigen-engaged B cells undergo directional migration to the T cell zone and form motile conjugates with helper T cells. PLOS Biology 3 1-13.

4. Tang, Q., Adams, J.Y., Tooley, A.J., Bi, M., Serra, P., Santamaria, P., Krummel, M.F.* and Bluestone, J.A.* 2006. Visualizing regulatory T cell control of autoimmune response in NOD diabetic mice. Nature Immunology, 7, 83-92

5. Moldovan MC, Sabbagh L, Breton G, Sekaly RP*and Krummel MF*. (*co-last authors) 2006. Triggering of T cell activation via CD4 dimers. J Immunol. 176(9):5438-45.31.

6.Friedman, R.S. Jacobelli, J, and Krummel, M.F. 2006. Surface-bound Chemokines Capture and Prime T cells For Synapse Formation. Nature Immunology  7, 1101-8.