Published online before print February 13, 2009

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(Journal of Leukocyte Biology. 2009;85:817-825.)
© 2009 Society for Leukocyte Biology

IFN--indoleamine-2,3 dioxygenase acts as a major suppressive factor in 4-1BB-mediated immune suppression in vivo

Young H. Kim^*, Beom K. Choi^*, Woo J. Kang^*, Kwang H. Kim^*, Sang W. Kang, Andrew L. Mellor, David H. Munn and Byoung S. Kwon^*,,1

^* Division of Cell and Immunobiology and R&D Center for Cancer Therapeutics, National Cancer Center, Kyonggi-do, Korea;
The Immunomodulation Research Center, University of Ulsan, Ulsan, Korea;
Medical College of Georgia, Immunotherapy Center, Augusta, Georgia, USA; and
Louisiana State University Eye Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA

¹ Correspondence: Division of Cell and Immunobiology and R&D Center for Cancer Therapeutics, National Cancer Center, 809 Madu, Ilsan, Goyang, Kyounggi-do, Korea 411-769. E-mail: bskwon{at}ncc.re.kr

ABSTRACT

It has been reported that 4-1BB triggering in vivo selectively suppressed the recall response of staphylococcal enterotoxin A (SEA)-specific CD4⁺ T cells, in which CD8⁺ T-derived TGF-β was involved. Here, we have examined an alternative mechanism for the 4-1BB-mediated CD4⁺ T suppression, as the neutralization of TGF-β is only effective in rescuing the SEA-specific recall response at high cellular concentrations. We show that this selective suppression of CD4⁺ T cells by 4-1BB triggering in vivo is mediated mainly by induction of indoleamine 2,3-dioxygenase (IDO) in an IFN--dependent manner. SEA-specific CD4⁺ T responses were suppressed partly by TGF-β-expressing CD8⁺ T cells, particularly CD11c⁺CD8⁺ T cells, but strongly inhibited by dendritic cells (DCs) expressing IDO. IFN- that increased IDO in DCs was produced primarily from CD11c⁺CD8⁺ T cells, which were expanded selectively by 4-1BB stimulation. CD4⁺, CD8⁺, and plasmacytoid DCs exerted a similar suppressive activity toward the SEA-specific CD4⁺ T cells. Neutralization of IFN- or IDO activity in vivo largely reversed the 4-1BB-mediated CD4⁺ T suppression. Collectively, these data indicate that 4-1BB-dependent suppression of SEA-specific CD4⁺ T responses was mediated mainly by IFN--dependent IDO induction and partially by TGF-β.

Key Words: SEA • T cells • costimulation

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