Early IL-17 Production by Intrahepatic T Cells Is Important for Adaptive Immune Responses in Viral Hepatitis

Hou, Lifei; Jie, Zuliang; Desai, Mayura; Liang, Yuejin; Soong, Lynn; Wang, Tian; Sun, Jiaren

doi:10.4049/jimmunol.1201970

Cited by 49 publications

(67 citation statements)

References 56 publications

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“…Betulin reduces serum levels of IFN-γ, TNF-α, and IL-6 in mice with hepatitis Several lines of evidence suggest that IFN-γ [16,17] , TNF-α [18,19] , IL-4 [20] , and IL-17 [21,22] promote hepatic damage, whereas IL-10 [23] protects the liver from injury, and IL-6 [18] has varying effects depending on the stage of Con A-induced hepatitis at which it is present. To ascertain whether betulin interfered with the systemic levels of these cytokines, we examined the serum levels of IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, and IL-17 by using a CBA kit.…”

Section: Resultsmentioning

confidence: 99%

Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

et al. 2016

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Hedyotis hedyotidea has been used in traditional Chinese medicine for the treatment of autoimmune diseases. However, the mechanisms underlying for the effect remain unknown. We previously showed that, among 11 compounds extracted from H hedyotidea, betulin produced the strongest suppressive effect on T cell activation. Here, we examined the hepatoprotective effects of betulin against acute autoimmune hepatitis in mice and the mechanisms underlying the effects. Freshly isolated mouse splenocytes were stimulated with concanavalin A (Con A, 5 μg/mL) in the presence of betulin, the cell proliferation was assessed with CSFE-dilution assay. Mice were injected with betulin (10, 20 mg· kg -1 ·d -1 , ip) for 3 d. One hour after the last injection, the mice were injected with Con A (15 mg/kg, iv) to induce acute hepatitis. Blood samples and liver tissues were harvested at 10 h after Con A injection, and serum transaminase levels and liver histopathology were detected; serum levels of proinflammatory cytokines, hepatic T lymphocyte ratios, and functional statuses of conventional T and NKT cells were also analyzed. Betulin (16 and 32 μmol/L) dose-dependently suppressed the proliferation of Con A-stimulated mouse splenocytes in vitro. In Con A-challenged mice, preinjection with betulin (20 mg· kg -1 ·d -1 ) significantly decreased the levels of proinflammatory cytokines IFN-γ, TNF-α and IL-6, and ameliorated liver injury. Furthermore, pretreatment with betulin (20 mg· kg -1 ·d -1 ) significantly inhibited the Con A-induced activation of NKT and conventional T cells, and decreased production of proinflammatory cytokines IFN-γ, TNF-α and IL-6 in these two cell populations. Betulin has immunomodulatory effect on overly activated conventional T and NKT cells and exerts hepatoprotective action in mouse autoimmune hepatitis. The findings provide evidence for the use of H hedyotidea and its constituent betulin in the treatment of autoimmune diseases.

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Section: Resultsmentioning

confidence: 99%

Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

et al. 2016

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“…18,25 Briefly, liver tissues were digested by collagenase IV (0.05%, Roche), followed by centrifugation (400g) at room temperature for 30 min over a 30%/70% discontinuous Percoll gradient (Sigma). The cells were collected from the interphase and then thoroughly washed.…”

Section: Isolation Of Intrahepatic Lymphocytesmentioning

confidence: 99%

“…injected at 2310 9 pfu/mouse to induce hepatitis as described previously. 18 In vivo antibody blocking To block the PD-1/PD-L1 pathway at the effector phase of Ad infection, Ad-infected mice were i.p. injected with 50 mg, monoclonal antibody (mAb) against PD-L1 (Clone: 10F.9G2, Biolegend, San Diego, CA, USA) on days 4 and 5 post-infection.…”

Section: Animalsmentioning

confidence: 99%

“…17 We have recently demonstrated that IFN-b induces hepatic IL-7 production shortly after adenoviral infection in the liver. 18 However, it is unclear whether hepatic IL-7 expression is linked to local CD8 1 T-cell functions or homeostasis. Emerging evidence suggests that in autoimmune type 1 diabetes, IL-7 suppressed PD-1 expression and maintained the survival of autoreactive T cells.…”

Section: Introductionmentioning

confidence: 99%

“…Based on these reports, 17,18,24 we hypothesized that IFN-Iinduced IL-7 secretion in the liver suppresses PD-1 expression in CD8 1 T cells and maintains their function and survival following acute viral infection. We tested this hypothesis using both wild type and IFN-a receptor knockout (IFNAR 2/2 ) mice that were infected with hepatotropic adenovirus (Ad).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Type 1 interferon-induced IL-7 maintains CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis

et al. 2014

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Type 1 interferon (IFN-I) promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by IFN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus (Ad) in IFN-a receptor knockout (IFNAR 2/2 ) and control mice. To disrupt signaling, monoclonal antibodies (mAbs) against IL-7 receptor alpha (IL-7Ra) or PD-L1 were i.p. injected. We found that CD8 1 T cells in IFNAR 2/2 mice were less effective than those in control mice. The reduced T-cell function was accompanied by increased levels of PD-1 expression, apoptosis and decreased IFN-c production. The lack of IFN-I signaling also impaired the expression of accessory molecules in both intrahepatic dendritic cell (DCs) and hepatocytes. PD-L1 was comparably and highly expressed on hepatocytes in both IFNAR 2/2 and control mice. Injection of PD-L1-specific mAb in IFNAR 2/2 mice reversed the compromised immune responses in the liver. Further investigation showed that hepatic IL-7 elevation was less pronounced in IFNAR 2/2 mice compared to the controls. A treatment with recombinant IL-7 suppressed PD-1 expression on CD8 1 T cells in vitro. Accordingly, blocking IL-7R signaling in vivo resulted in increased PD-1 expression on CD8 1 T cells in Ad-infected mice. Collectively, the results suggest that IFN-I-induced hepatic IL-7 production maintains antiviral CD8 1 T-cell responses and homeostasis by suppressing PD-1 expression in acute viral hepatitis.

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IL‐33 promotes innate IFN‐γ production and modulates dendritic cell response in LCMV‐induced hepatitis in mice

et al. 2015

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Recent studies have revealed IL-33 as a key factor in promoting antiviral T-cell responses. However, it is less clear as to how IL-33 regulates innate immunity. In this study, we infected wild-type (WT) and IL-33−/− mice with lymphocytic choriomeningitis virus (LCMV) and demonstrated an essential role of infection-induced IL-33 expression for robust innate IFN-γ production in the liver. We first shown that IL-33 deficiency resulted in a marked reduction in the number of IFN-γ+ γδ T and NK cells, but an increase in that of IL-17+ γδ T cells at 16 hours post-infection. Recombinant IL-33 (rIL-33) treatment could reverse such deficiency via increasing IFN-γ-producing γδ T and NK cells, and inhibiting IL-17+ γδ T cells. We also found that rIL-33-induced type 2 innate lymphoid cells (ILC2) were not involved in T-cell responses and liver injury, since the adoptive transfer of ILC2s neither affected the IFN-γ and TNF-α production in T cells, nor liver transferase levels in LCMV-infected mice. Interestingly, we found that while IL-33 was not required for costimulatory molecule expression, it was critical for DC proliferation and cytokine production. Together, this study highlights an essential role of IL-33 in regulating innate IFN-γ-production and DC function during viral hepatitis.

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Early IL-17 Production by Intrahepatic T Cells Is Important for Adaptive Immune Responses in Viral Hepatitis

Cited by 49 publications

References 56 publications

Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

Type 1 interferon-induced IL-7 maintains CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis

IL‐33 promotes innate IFN‐γ production and modulates dendritic cell response in LCMV‐induced hepatitis in mice

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