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Molecular and Cellular Biology, October 2006, p. 7155-7166, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.00507-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Persistence of Cooperatively Stabilized Signaling Clusters Drives T-Cell Activation{dagger}

Stephen C. Bunnell,1,{ddagger}* Andrew L. Singer,2,{ddagger},§ David I. Hong,1 Berri H. Jacque,3 Martha S. Jordan,2 Maria-Cristina Seminario,4 Valarie A. Barr,1 Gary A. Koretzky,2 and Lawrence E. Samelson1

Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland,1 Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania,2 Laboratory of Cellular and Molecular Biology, NIA, National Institutes of Health, Baltimore, Maryland,4 Program in Immunology, Tufts University School of Medicine, Boston, Massachusetts3

Received 22 March 2006/ Returned for modification 5 May 2006/ Accepted 11 July 2006

Antigen recognition triggers the recruitment of the critical adaptor protein SLP-76 to small macromolecular clusters nucleated by the T-cell receptor (TCR). These structures develop rapidly, in parallel with TCR-induced increases in tyrosine phosphorylation and cytosolic calcium, and are likely to contribute to TCR-proximal signaling. Previously, we demonstrated that these SLP-76-containing clusters segregate from the TCR and move towards the center of the contact interface. Neither the function of these clusters nor the structural requirements governing their persistence have been examined extensively. Here we demonstrate that defects in cluster assembly and persistence are associated with defects in T-cell activation in the absence of Lck, ZAP-70, or LAT. Clusters persist normally in the absence of phospholipase C-{gamma}1, indicating that in the absence of a critical effector, these structures are insufficient to drive T-cell activation. Furthermore, we show that the critical adaptors LAT and Gads localize with SLP-76 in persistent clusters. Mutational analyses of LAT, Gads, and SLP-76 indicated that multiple domains within each of these proteins contribute to cluster persistence. These data indicate that multivalent cooperative interactions stabilize these persistent signaling clusters, which may correspond to the functional complexes predicted by kinetic proofreading models of T-cell activation.

* Corresponding author. Present address: Department of Pathology, Tufts University Medical School, Jaharis Bldg., Rm. 512, 150 Harrison Ave., Boston, MA 02111. Phone: (617) 636-2174. Fax: (617) 636-2990. E-mail: Stephen.Bunnell{at}tufts.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} S.C.B. and A.L.S. contributed equally to this work.

§ Present address: Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD 21287.

Molecular and Cellular Biology, October 2006, p. 7155-7166, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.00507-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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