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A Large T Cell Invagination with CD2 Enrichment Resets Receptor Engagement in the Immunological Synapse¹

Kentner Singleton^2,*, Nadia Parvaze^2,*, Kavyya R. Dama^*, Kenneth S. Chen^*, Paula Jennings^*, Bozidar Purtic^*, Michael D. Sjaastad, Christopher Gilpin, Mark M. Davis and Christoph Wülfing^3,*,

^* Center for Immunology and Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Bio-X Program and Department of Microbiology and Immunology, Stanford University, and Howard Hughes Medical Institute, Stanford, CA 94305

T cell activation is driven by the TCR and complemented by costimulation. We have studied the dynamics of ligand-engagement of the costimulatory receptor CD2 in T cell/APC couples. Thousands of ligand-engaged CD2 molecules were included in a large T cell invagination at the center of the cellular interface within 1 min of cell couple formation. The structure and regulation of this invagination shared numerous features with phagocytosis and macropinocytosis. Three observations further characterize the invagination and the inclusion of CD2: 1) numerous ligand-engaged receptors were enriched in and internalized through the T cell invagination, none as prominently as CD2; 2) dissolution of the T cell invagination and CD2 engagement were required for effective proximal T cell signaling; and 3) the T cell invagination was uniquely sensitive to the affinity of the TCR for peptide-MHC. Based on this characterization, we speculate that the T cell invagination, aided by CD2 enrichment, internalizes parts of the TCR signaling machinery to reset T cell signaling upon agonist-mediated, stable APC contact.

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 grants from the National Institutes of Health (to C.W.) and the Howard Hughes Medical Institute (to M.M.D.).

² K.S. and N.P. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Christoph Wülfing, Center for Immunology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9093. E-mail address: christoph.wuelfing{at}UTSouthwestern.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; DLC1, dynein L chain 1; EM, electron microscopy; LAT, linker of activated T cells; MCC, moth cytochrome c; Pak, p21-activated kinase.

⁵ The online version of this article contains supplemental material.