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Regulates Stability of the Peripheral Adhesion Ring Junction and Contributes to the Sensitivity of Target Cell Lysis by CTL1
* Department of Microbiology and Immunology and Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107;
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016; and
Blood Systems Research Institute and the Departments of Laboratory Medicine and Medicine, University of California, San Francisco, CA 94118
Destruction of virus-infected cells by CTL is an extremely sensitive and efficient process. Our previous data suggest that LFA-1-ICAM-1 interactions in the peripheral supramolecular activation cluster (pSMAC) of the immunological synapse mediate formation of a tight adhesion junction that might contribute to the sensitivity of target cell lysis by CTL. Herein, we compared more (CD8+) and less (CD4+) effective CTL to understand the molecular events that promote efficient target cell lysis. We found that abrogation of the pSMAC formation significantly impaired the ability of CD8+ but not CD4+ CTL to lyse target cells despite having no effect of the amount of released granules by both CD8+ and CD4+ CTL. Consistent with this, CD4+ CTL break their synapses more often than do CD8+ CTL, which leads to the escape of the cytolytic molecules from the interface. CD4+ CTL treatment with a protein kinase C
inhibitor increases synapse stability and sensitivity of specific target cell lysis. Thus, formation of a stable pSMAC, which is partially controlled by protein kinase C, functions to confine the released lytic molecules at the synaptic interface and to enhance the effectiveness of target cell lysis.
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 NIH grants to Y.S. (AI3254), P.J.N. (AI067854), and M.L.D. (AI44931; AI3254). A.M.B. was supported in part by NRSA training grant T32-CA 0983.
2 Current address: National Institute of Allergy and Infectious Diseases/Laboratory of Cellular and Molecular Immunology, National Institutes of Health, Building 4, Room 431, 4 Center Drive, Bethesda, MD 20892.
3 Address correspondence and reprint requests to Dr. Yuri Sykulev, Department of Microbiology and Immunology, Kimmel Cancer Center, BLSB 706, Thomas Jefferson University, Philadelphia, PA 19107. E-mail address: ysykulev{at}lac.jci.tju.edu
4 Abbreviations used in this paper: pMHC, peptide-MHC; cSMAC, central supramolecular activation cluster; dSMAC, distal supramolecular activation cluster; IS, immunological synapse; PKC, protein kinase C; pSMAC, peripheral supramolecular activation cluster; RU, relative units; TIRF, total internal reflection fluorescence.
5 The online version of this article contains supplemental material.
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