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* Department of Surgery,
Department of Immunology,
Departments of Infectious Diseases and Microbiology, and
Departments of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA 15213;
¶ Department of Immunopathology, Sanquin Research, Centraal Laboratorium van de Bloedtransfusiedienst and Landsteiner Laboratory, Academic Medical Center, Amsterdam, The Netherlands; and
|| University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
CD8+ T cells have been shown to be capable of either suppressing or promoting immune responses. To reconcile these contrasting regulatory functions, we compared the ability of human effector and memory CD8+ T cells to regulate survival and functions of dendritic cells (DC). We report that, in sharp contrast to the effector cells (CTLs) that kill DCs in a granzyme B- and perforin-dependent mechanism, memory CD8+ T cells enhance the ability of DCs to produce IL-12 and to induce functional Th1 and CTL responses in naive CD4+ and CD8+ T cell populations. Moreover, memory CD8+ T cells that release the DC-activating factor TNF-
before the release of cytotoxic granules induce DC expression of an endogenous granzyme B inhibitor PI-9 and protect DCs from CTL killing with similar efficacy as CD4+ Th cells. The currently identified DC-protective function of memory CD8+ T cells helps to explain the phenomenon of CD8+ T cell memory, reduced dependence of recall responses on CD4+ T cell help, and the importance of delayed administration of booster doses of vaccines for the optimal outcome of immunization.
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 National Institutes of Health Grants CA095128 and CA101944.
2 Address correspondence and reprint requests to Dr. Pawel Kalinski, Department of Surgery, University of Pittsburgh, Hillman Cancer Center, University of Pittsburgh Cancer Institute Research Pavilion, Room 1.46b, 5117 Center Avenue, Pittsburgh, PA 15213-1863. E-mail address: kalinskip{at}upmc.edu
3 Abbreviations used in this paper: DC, dendritic cell; rhu, recombinant human; SEB, Staphylococcus enterotoxin B; s, soluble; CMA, concanamycin A; NAO, nonyl acridine orange; LT, lymphotoxin; PAMP, pathogen-associated molecular pattern; DAMP, damage-associated molecular pattern.
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