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LFA-1-Mediated T Cell Costimulation through Increased Localization of TCR/Class II Complexes to the Central Supramolecular Activation Cluster and Exclusion of CD45 from the Immunological Synapse¹

Beth Graf^*, Timothy Bushnell and Jim Miller^2,*,

^* David H. Smith Center for Vaccine Biology and Immunology, Center for Pediatric Biomedical Research, Aab Institute for Biomedical Research, and Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642

T cell activation is associated with a dramatic reorganization of cell surface proteins and associated signaling components into discrete subdomains within the immunological synapse in T cell:APC conjugates. However, the signals that direct the localization of these proteins and the functional significance of this organization have not been established. In this study, we have used wild-type and LFA-1-deficient, DO11.10 TCR transgenic T cells to examine the role of LFA-1 in the formation of the immunological synapse. We found that coengagement of LFA-1 is not required for the formation of the central supramolecular activation cluster (cSMAC) region, but does increase the accumulation of TCR/class II complexes within the cSMAC. In addition, LFA-1 is required for the recruitment and localization of talin into the peripheral supramolecular activation cluster region and exclusion of CD45 from the synapse. The ability of LFA-1 to increase the amount of TCR engaged during synapse formation and segregate the phosphatase, CD45, from the synapse suggests that LFA-1 might enhance proximal TCR signaling. To test this, we combined flow cytometry-based cell adhesion and calcium-signaling assays and found that coengagement of LFA-1 significantly increased the magnitude of the intracellular calcium response following Ag presentation. These data support the idea that in addition to its important role on regulating T cell:APC adhesion, coengagement of LFA-1 can enhance T cell signaling, and suggest that this may be accomplished in part through the organization of proteins within the immunological synapse.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant RO1-AI48237 from the National Institutes of Health (to J.M.).

² Address correspondence and reprint requests to Dr. Jim Miller, Center for Vaccine Biology and Immunology, University of Rochester, Box 609, 601 Elmwood Avenue, Rochester, NY 14642-8609. E-mail address: jim_miller{at}urmc.rochester.edu

³ Abbreviations used in this paper: pSMAC, peripheral supramolecular activation cluster; CD18KO, CD18 knockout; cSMAC, central supramolecular activation cluster; PKC, protein kinase C; WT, wild type.

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