Ly6Chi monocytes regulate T cell responses in viral hepatitis
Jiangao Zhu, Huiyao Chen, Xiaopei Huang, Songfu Jiang, Yiping Yang
Jiangao Zhu, Huiyao Chen, Xiaopei Huang, Songfu Jiang, Yiping Yang
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Research Article Immunology Virology

Ly6Chi 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 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.

Authors

Jiangao Zhu, Huiyao Chen, Xiaopei Huang, Songfu Jiang, Yiping Yang

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Figure 4

Recruitment of Ly6Chi monocytes to the liver upon adenoviral infection is dependent on CCR2.

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Recruitment of Ly6Chi monocytes to the liver upon adenoviral infection i...
(A and B) Wild-type (WT) or CCR2–/– mice were injected intravenously with recombinant adenovirus encoding LacZ (Ad). (A) On days 3, 7, and 10 after infection, cells from liver tissues of Ad-infected WT or CCR2–/– mice were analyzed for Ly6Chi monocytes by flow cytometry, and the total numbers of Ly6Chi monocytes in the liver and the bone marrow (BM) are indicated. Left: Mean cell numbers of Ly6Chi monocytes ± SEM in the liver. Right: Mean cell numbers of Ly6Chi monocytes ± SEM in the BM. ***P < 0.001, determined by multiple Student’s t test, n = 5 mice per group. (B) Ten days after infection, liver tissues were harvested, and cryosections were stained for LacZ expression by X-gal histochemistry. Scale bars: 100 μm. (C and D) A total of 2 × 104 purified naive OT-1 CD8+ T cells (Thy1.1+) were adoptively transferred into congenic WT or CCR2–/– mice (Thy1.2+), which were subsequently infected intravenously with Ad-OVA. Seven days later, intrahepatic cells were stained with anti-CD8, anti-Thy1.1, and anti–IFN-γ intracellularly after restimulation in vitro for 6 hours with 5 μg/ml brefeldin A and 2 μg/ml of OVA peptide (257SIINFEKL264). The percentage of clonotypic OT-1 CD8+ cells among total lymphocytes are shown in C (top), and the absolute number of clonotypic cells ± SEM in the liver are indicated in D (left). The percentage of IFN-γ–producing clonotypic cells among T lymphocytes is shown in C (bottom), and the total number of IFN-γ–producing clonotypic cells ± SD in the liver are indicated in D (right). ***P < 0.001, determined by multiple Student’s t test, n = 5 mice per group. Data shown are representative of 3 independent experiments.