Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection

• Published in: The Journal of immunology (1950) 2012-07, Vol.189 (2), p.755-766
• Main Authors: Moorman, Jonathan P, Wang, Jia M, Zhang, Ying, Ji, Xiao J, Ma, Cheng J, Wu, Xiao Y, Jia, Zhan S, Wang, Ke S, Yao, Zhi Q
• Format: Article
• Language: English
• Subjects: Apoptosis Regulatory Proteins - physiology; Cell Proliferation; Forkhead Transcription Factors - biosynthesis; Forkhead Transcription Factors - physiology; Hepatitis C virus; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - metabolism; Hepatitis C, Chronic - pathology; Humans; Interleukin-2 Receptor alpha Subunit - biosynthesis; Interleukin-2 Receptor alpha Subunit - physiology; Pilot Projects; Receptors, Immunologic - physiology; Signal Transduction - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - pathology; T-Lymphocyte Subsets - virology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; T-Lymphocytes, Regulatory - virology; Viremia - immunology; Viremia - metabolism; Viremia - pathology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1200162

Hepatitis C virus (HCV) is remarkable at disrupting human immunity to establish chronic infection. Upregulation of inhibitory signaling pathways (such as T cell Ig and mucin domain protein-3 [Tim-3]) and accumulation of regulatory T cells (Tregs) play pivotal roles in suppressing antiviral effector T cell (Teff) responses that are essential for viral clearance. Although the Tim-3 pathway has been shown to negatively regulate Teffs, its role in regulating Foxp3(+) Tregs is poorly explored. In this study, we investigated whether and how the Tim-3 pathway alters Foxp3(+) Treg development and function in patients with chronic HCV infection. We found that Tim-3 was upregulated, not only on IL-2-producing CD4(+)CD25(+)Foxp3(-) Teffs, but also on CD4(+)CD25(+)Foxp3(+) Tregs, which accumulate in the peripheral blood of chronically HCV-infected individuals when compared with healthy subjects. Tim-3 expression on Foxp3(+) Tregs positively correlated with expression of the proliferation marker Ki67 on Tregs, but it was inversely associated with proliferation of IL-2-producing Teffs. Moreover, Foxp3(+) Tregs were found to be more resistant to, and Foxp3(-) Teffs more sensitive to, TCR activation-induced cell apoptosis, which was reversible by blocking Tim-3 signaling. Consistent with its role in T cell proliferation and apoptosis, blockade of Tim-3 on CD4(+)CD25(+) T cells promoted expansion of Teffs more substantially than Tregs through improving STAT-5 signaling, thus correcting the imbalance of Foxp3(+) Tregs/Foxp3(-) Teffs that was induced by HCV infection. Taken together, the Tim-3 pathway appears to control Treg and Teff balance through altering cell proliferation and apoptosis during HCV infection.