Interleukin-10 increases Th1 cytokine production and cytotoxic potential in human papillomavirus-specific CD8(+) cytotoxic T lymphocytes.
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.
Santin
A D
AD
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199, USA.
Hermonat
P L
PL
Ravaggi
A
A
Bellone
S
S
Pecorelli
S
S
Roman
J J
JJ
Parham
G P
GP
Cannon
M J
MJ
D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D027383:Papillomaviridae / Q000276:immunology*; D030361:Papillomavirus Infections / Q000821:virology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000821:virology
D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D016753:Interleukin-10