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Rapid Up-Regulation and Granule-Independent Transport of Perforin to the Immunological Synapse Define a Novel Mechanism of Antigen-Specific CD8⁺ T Cell Cytotoxic Activity¹

George Makedonas^2,*, Pinaki P. Banerjee^2,, Rahul Pandey, Adam R. Hersperger^*, Keri B. Sanborn, Gareth A. D. Hardy, Jordan S. Orange^2, and Michael R. Betts^2,3,*

^* Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104; Children’s Hospital of Philadelphia, Division of Immunology, Philadelphia, PA 19104; and Department of Pathology, Case Western Reserve University, Cleveland, OH 44106

CTL are endowed with the ability to eliminate pathogens through perforin-mediated cytotoxic activity. The mechanism for perforin-mediated Ag-specific killing has been solely attributed to cytotoxic granule exocytosis from activated CD8⁺ T cells. In this study, we redefine this mechanism, demonstrating that virus-specific CD8⁺ T cells rapidly up-regulate perforin in response to stimulation temporally with IFN- and CD107a expression. Following Ag-specific activation, newly synthesized perforin rapidly appears at the immunological synapse, both in association with and independent of cytotoxic granules, where it functions to promote cytotoxicity. Our work suggests a novel mechanism of CTL cytotoxicity and identifies a novel correlate of CD8⁺ T cell-mediated immunity.

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 the following grants and organizations: National Institutes of Health Grants AI076066 (to M.R.B.), AI067946 (to J.S.O.), and AI079731 (to J.S.O.) and the W. W. Smith Foundation (to M.R.B.).

² G.M. and P.P.B. made equivalent contributions to this manuscript, as did J.S.O. and M.R.B.

³ Address correspondence and reprint requests to Dr. Michael R. Betts, Department of Microbiology, 522E Johnson Pavilion, 3610 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104. E-mail address: betts{at}mail.med.upenn.edu

⁴ Abbreviations used in this paper: MFI, mean fluorescence intensity; CHX, cycloheximide.