Published online before print December 17, 2007
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,1
* 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
2Correspondence: Department of Microbiology, Center for Viral Disease Research, Bio-Marker Research Center for Personalized Therapy, Inje University College of Medicine, Busan 614-735, Korea. 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 • viral persistence
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