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Journal of Virology, May 2000, p. 4729-4737, Vol. 74, No. 10
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

Alessandro D. Santin,1,2,* Paul L. Hermonat,1 Antonella Ravaggi,1,2 Stefania Bellone,1,2 Sergio Pecorelli,2 Juan J. Roman,1 Groesbeck P. Parham,1 and Martin J. Cannon3

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-gamma ), tumor necrosis factor alpha, and transforming growth factor beta , 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 alpha  and beta  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-gamma 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-gamma 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.

Journal of Virology, May 2000, p. 4729-4737, Vol. 74, No. 10
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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