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Published online before print December 17, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0307168

Received for publication March 17, 2007.
Revised November 1, 2007.
Accepted for publication November 12, 2007.

Article

Blocking of monocyte-associated B7-H1 (CD274) enhances HCV-specific T cell immunity in chronic hepatitis C infection

Hye-Young Jeong ^*, Youn-Jae Lee , Su-Kil Seo ^*, Soo-Woong Lee ^*, Sung-Jae Park , Jeong-Nyeo Lee , Hae-Sook Sohn , Sheng Yao ^||, Lieping Chen ^||, and Inhak Choi ^*@

Departments of *Microbiology, Center for Viral Disease Research, Bio-Marker Research Center for Personalized Therapy, Internal Medicine, Laboratory Medicine, and Preventive Medicine, Inje University College of Medicine, Busan, Korea; and ^||Departments of Dermatology and Oncology and the Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

^@ To whom correspondence should be addressed. E-mail: miccih{at}inje.ac.kr.

	Abstract

The establishment of a chronic hepatitis C (CHC) infection is associated with defective HCV-specific T cell responses. Recent studies suggest that negative T cell regulators such as programmed death 1 (PD-1) contribute to the impairment of virus-specific T cell functions in chronic viral infections. However, the implication of peripheral monocytes from CHC patients in the inhibition of HCV-specific T cell responses is only partially defined. In this study, we found that B7-H1, a ligand of PD-1, was significantly up-regulated on monocytes of CHC patients. Proliferation of T cells in response to anti-CD3 antibody was directly suppressed by B7-H1⁺CD14⁺ monocytes, and this suppression was reversed by addition of antagonistic B7-H1 mAb. Furthermore, blocking of monocyte-associated B7-H1 (moB7-H1) significantly enhanced the frequency of IFN--producing, HCV-specific CD4⁺ and CD8⁺ effector T cells and the production of Th1 cytokines, such as IL-2 but not Th2 cytokines, including IL-4 and IL-10. Upon B7-H1 blockade, production of perforin was also increased in CD8⁺ T cells stimulated with HCV peptides. Our findings suggest that moB7-H1 inhibits HCV-specific CD4⁺ and CD8⁺ T lymphocyte proliferation and suppresses Th1 cytokine production and perforin secretion. Blockade of the B7-H1 pathway thus represents an attractive approach in the treatment of chronic HCV infection.

Key Words: cosignaling molecule • programmed death 1

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