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Journal of Virology, May 2000, p. 4729-4737, Vol. 74, No. 10
Division of Gynecologic Oncology, Department
of Obstetrics and Gynecology,1 and
Department of Microbiology and
Immunology,3 University of Arkansas for Medical
Sciences, Little Rock, Arkansas, and Division of
Gynecologic Oncology, University of Brescia, Brescia,
Italy2
Received 28 December 1999/Accepted 23 February 2000
Interleukin-10 (IL-10) is widely known as an immunosuppressive
cytokine by virtue of its ability to inhibit macrophage-dependent antigen presentation, T-cell proliferation, and Th1 cytokine secretion. However, several studies have challenged the perception of IL-10 solely
as an immunosuppressive cytokine. As part of an investigation on
potentiation of the cytotoxic activity of human papillomavirus E7-specific CD8+ cytotoxic T lymphocytes (CTL) for adoptive
transfusions to cervical cancer patients, we found that IL-10 in
combination with IL-2, unlike several other combinations, including
IL-2 with IL-12, gamma interferon (IFN-
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Interleukin-10 Increases Th1 Cytokine Production
and Cytotoxic Potential in Human Papillomavirus-Specific
CD8+ Cytotoxic T Lymphocytes
), tumor necrosis factor
alpha, and transforming growth factor
, was able to consistently
increase cytotoxicity. This augmentation in cytotoxic activity
correlated with a significant increase in the cytoplasmic accumulation
of perforin as detected by fluorescence-activated cell sorter. Surface
expression of both the
and
chains of the CD8 heterodimeric
coreceptor and CD56 molecules was increased by exposure of CTL to
IL-10. More importantly, we found that administration of IL-10 in
combination with IL-2 after antigen stimulation consistently increased
the intracellular expression of Th1 cytokines (i.e., IFN-
and IL-2)
compared to results for control CD8+ T cells cultured in
IL-2 alone. In kinetic studies, proliferation, intracellular perforin
levels, cytotoxic activity, and IFN-
expression were consistently
elevated in CTL cultures containing IL-10 compared to control cultures,
both at early and late time points following stimulation. In contrast,
intracellular IL-2 expression was consistently increased only at early
time points following stimulation with autologous tumor cells or
solid-phase anti-CD3 antibody. Taken together, these data support the
use of IL-10 in combination with IL-2 for the in vitro expansion and
potentiation of tumor-specific CTL for clinical use in the therapy of cancer.
*
Corresponding author. Mailing address: UAMS Medical
Center, Division of Gynecologic Oncology, University of Arkansas, 4301 W. Markham, Little Rock, AR 72205-7199. Phone: (501) 686-7162. Fax:
(501) 686-8091. E-mail: cannonmartin{at}exchange.uams.edu.
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