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Regulated Movement of CD4 In and Out of the Immunological Synapse¹

Henry Kao^*,, Joseph Lin^*, Dan R. Littman, Andrey S. Shaw^*, and Paul M. Allen^2,*

^* Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; Allergan Inc., Irvine, CA 92612; Howard Hughes Medical Institute and Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016; and Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110

The mechanism underlying the transient accumulation of CD4 at the immunological synapse (IS) and its significance for T cell activation are not understood. To investigate these issues, we mutated a serine phosphorylation site (S408) in the cytoplasmic tail of murine CD4. Preventing phosphorylation of S408 did not block CD4 recruitment to the IS; rather, it blocked the ability of CD4 to leave the IS. Surprisingly, enhanced and prolonged CD4 accumulation at the supramolecular activation cluster in the contact area had no functional consequence for T cell activation, cytokine production, or proliferation. Protein kinase C (PKC)-deficient T cells also displayed enhanced and prolonged accumulation of wild-type CD4 at the IS, indicating that is the critical PKC isoform involved in CD4 movement. These findings suggest a model wherein recruitment of CD4 to the IS allows its phosphorylation by PKC and subsequent removal from the IS. Thus, an important role for PKC in T cell activation involves its recruitment to the IS, where it phosphorylates specific substrates that help to maintain the dynamism of protein turnover at the IS.

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 AI24157 and AI071195 from The National Institutes of Health.

² Address correspondence and reprint requests to Dr. Paul M. Allen, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO. E-mail address: pallen{at}wustl.edu

³ Abbreviations used in this paper: IS, immunological synapse; SMAC, supramolecular activation cluster; PKC, protein kinase C ; YFP, yellow-fluorescent protein; CFP, cyan-fluorescent protein; WT, wild type; Hb, hemoglobin.

⁴ The online version of this article contains supplemental material.