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International Immunology Advance Access published online on July 18, 2005
International Immunology, doi:10.1093/intimm/dxh292
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© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org
Received November 1, 2004
Accepted June 3, 2005

Article

Ex vivo expanded human CD4+ regulatory NKT cells suppress expansion of tumor antigen-specific CTLs

Takuya Osada 1, Michael A. Morse 2, H. Kim Lyerly 3, and Timothy M. Clay 1*

1 Program in Molecular Therapeutics, Duke University Medical Center, 401 MSRB, Research Drive, Durham, NC 27710, USA; Department of Surgery, Duke University Medical Center, 401 MSRB, Research Drive, Durham, NC 27710, USA
2 Program in Molecular Therapeutics, Duke University Medical Center, 401 MSRB, Research Drive, Durham, NC 27710, USA; Departments of Medicine, Duke University Medical Center, 401 MSRB, Research Drive, Durham, NC 27710, USA
3 Program in Molecular Therapeutics, Duke University Medical Center, 401 MSRB, Research Drive, Durham, NC 27710, USA; Department of Surgery, Duke University Medical Center, 401 MSRB, Research Drive, Durham, NC 27710, USA; Departments of Immunology and Pathology, Duke University Medical Center, 401 MSRB, Research Drive, Durham, NC 27710, USA

* To whom correspondence should be addressed.
Timothy M. Clay, E-mail: tim.clay{at}duke.edu


  Abstract

NKT cells can produce large amounts of both Th1- and Th2-type cytokines and are an important regulatory cell type. To elucidate their role in acquired immunity, we examined the effect of human V{alpha}24+V{beta}11+ NKT cells or CD1d-specific ligand {alpha}-galactosylceramide ({alpha}GalCer) on the in vitro generation of antigen-specific CTLs from PBMCs using autologous MART-1(26-35) peptide-pulsed dendritic cells as stimulators. Flow cytometry using tetramer for MART-1(26-35) peptide revealed that NKT cells have inhibitory effects on CTL generation. Cytokine analysis using cytometric bead array assay and ELISA showed higher IL-4 and IL-10 secretion in the {alpha}GalCer(+) and/or NKT cell(+) culture setting, whereas IL-13 secretion in the culture was not affected by the presence of {alpha}GalCer. The CD4+ NKT cell subset seemed to play a major role in this inhibitory effect by secreting large amounts of Th2-type cytokines. Interestingly however, unlike recent reports utilizing mouse models, IL-13 was not a main effector molecule in our human system. Culture with {alpha}GalCer in the presence of cytokine-neutralizing antibodies for the Th2 cytokines, IL-4, IL-5 and IL-10, resulted in enhanced CTL generation, suggesting the dominant role of Th2 cytokines over Th1 cytokines. Thus, CD4+ NKT cells can work as immunoregulatory T cells that suppress anti-tumor immune response and, therefore, NKT cells or {alpha}GalCer could be used as therapeutic modalities to modulate systemic immune responses, such as autoimmune diseases. Conversely, the use of NKT cells along with anti-Th2 cytokine-neutralizing antibodies or CD4-negative NKT cell subset could enhance the generation of antigen-specific CTLs for adoptive immunotherapy.

Keywords: CTL; cytokines; dendritic cell; tumor immunity; T lymphocytes.
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