Ly6C^hi monocytes regulate T cell responses in viral hepatitis.

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 Ly6C^hi monocytes to the liver in a CCR2-dependent manner. These recruited Ly6C^hi monocytes suppressed CD8⁺ and CD4⁺ T cell responses to adenoviral infection, leading to a delay in viral clearance. In vivo depletion of Ly6C^hi 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 Ly6C^hi 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 Ly6C^hi monocytes. These findings suggest a critical role for Ly6C^hi 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.