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Critically Regulates the Proliferation and Survival of Pathogen-Specific T Cells in Murine Listeriosis1
* Institut für Medizinische Mikrobiologie and
Institut für Experimentelle Innere Medizin, Otto-von-Guericke Universität Magdeburg, Magdeburg;
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich;
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene and
¶ Abteilung für Neuropathologie, Klinikum der Universität zu Köln, Cologne, Germany
Protein kinase C-
(PKC-) is essential for the activation of T cells in autoimmune disorders, but not in viral infections. To study the role of PKC- in bacterial infections, PKC-–/– and wild-type mice were infected with Listeria monocytogenes (LM). In primary and secondary listeriosis, the numbers of LM-specific CD8 and CD4 T cells were drastically reduced in PKC-–/– mice, resulting in increased CFUs in spleen and liver of both PKC-–/– C57BL/6 and BALB/c mice. Furthermore, immunization with peptide-loaded wild-type dendritic cells induced LM-specific CD4 and CD8 T cells in wild-type but not in PKC-–/– mice. In listeriosis, transfer of wild-type T cells into PKC-–/– mice resulted in a normal control of Listeria, and, additionally, a selective expression of PKC- in LM-specific T cells was sufficient to drive a normal proliferation and survival of these T cells in LM-infected PKC-–/– recipients, illustrating a cell-autonomous function of PKC- in LM-specific T cells. Conversely, adoptively transferred PKC-–/– T cells were partially rescued from cell death and proliferated in LM-infected wild-type recipients, demonstrating that a PKC- deficiency of LM-specific T cells can be partially compensated for by a wild-type environment. Additionally, in vitro experiments showed that only the addition of IL-2, but not an inhibition of caspase-3, induced proliferation and prevented death of PKC-–/– T cells stimulated with LM-infected wild-type dendritic cells, further demonstrating that the impaired proliferation and survival of PKC-–/– T cells in listeriosis is not intrinsically fixed and can be experimentally improved.
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 in part by grants from the Bundesministerium für Bildung und Forschung (NBL3/2, 01ZZ0407) and the Deutsche Forschungsgemeinschaft (GRK 1167, De 486/6-3, Schl 392/6-1, SFB 575 TP8).
2 Address correspondence and reprint requests to Dr. Dirk Schlüter, Institut für Medizinische Mikrobiologie, Otto-von-Guericke Universität Magdeburg, Leipzigerstrasse 44, 39120 Magdeburg, Germany. E-mail address: dirk.schlueter{at}medizin.uni-magdeburg.de
3 Abbreviations used in this paper: PKC-, protein kinase C-; BMDC, bone marrow-derived DC; DC, dendritic cell; LCMV, lymphocytic choriomeningitis virus; LM, Listeria monocytogenes; LMgp, recombinant LM expressing glycoprotein of LCMV; LMova, recombinant OVA-expressing LM; LLO, listeriolysin O; MLN, mesenteric lymph node; p.i., postinfection; WT, wild type; Z-VAD-FMK, Val-Ala-Asp-fluoromethylketone.
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