Ly6Chi monocytes regulate T cell responses in viral hepatitis

JCI Insight. 2016 Oct 20;1(17):e89880. doi: 10.1172/jci.insight.89880.

Abstract

Viral hepatitis remains a global health challenge despite recent progress in the development of more effective therapies. Although virus-specific CD8+ and CD4+ T cell responses are essential for viral clearance, it remains largely unknown what regulates T cell-mediated viral clearance. Thus, a better understanding of the regulation of anti-viral T cell immunity would be critical for the design of more effective therapies for viral hepatitis. Using a model of adenovirus-induced hepatitis, here we showed that adenoviral infection induced recruitment of Ly6Chi monocytes to the liver in a CCR2-dependent manner. These recruited Ly6Chi monocytes suppressed CD8+ and CD4+ T cell responses to adenoviral infection, leading to a delay in viral clearance. In vivo depletion of Ly6Chi monocytes markedly enhanced anti-viral T cell responses and promoted viral clearance. Mechanistically, we showed that induction of iNOS and the production of NO by Ly6Chi monocytes are critical for the suppression of T cell responses. In addition, a contact-dependent mechanism mediated by PD-1 and PD-L1 interaction is also required for T cell suppression by Ly6Chi monocytes. These findings suggest a critical role for Ly6Chi monocytes in the regulation of T cell immunity in viral hepatitis and may provide new insights into development of more effective therapies for treating viral hepatitis based on targeting the immunosuppressing monocytes.

Publication types

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

MeSH terms

  • Animals
  • B7-H1 Antigen / metabolism
  • Disease Models, Animal
  • Hepatitis, Viral, Animal / immunology*
  • Liver / immunology
  • Liver / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Monocytes / immunology*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, CCR2 / immunology
  • T-Lymphocytes / immunology*

Substances

  • B7-H1 Antigen
  • Ccr2 protein, mouse
  • Cd274 protein, mouse
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, CCR2
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse