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

J Immunol. 2012 Jul 15;189(2):755-66. doi: 10.4049/jimmunol.1200162. Epub 2012 Jun 15.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis Regulatory Proteins / physiology
  • Cell Proliferation
  • Forkhead Transcription Factors / biosynthesis
  • Forkhead Transcription Factors / physiology
  • 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


  • Apoptosis Regulatory Proteins
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, Immunologic
  • TIGIT protein, human