Dynamic analysis of CD127 expression on memory CD8 T cells from patients with chronic hepatitis B during telbivudine treatment

Lv, Guoliang; Ying, Linjung; Ma, Wenjiang; Jin, Xi; Zheng, Lin; Li, Lanjuan; Yang, Yida

doi:10.1186/1743-422x-7-207

Cited by 16 publications

(19 citation statements)

References 18 publications

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“…19,20 Coincidently, clinical investigations reported that exhausted CD8 1 T cells downregulated their cell surface expression of the a chain of the IL-7 receptor (IL-7R; CD127) in chronic hepatitis B virus and hepatitis C virus patients. 14,21,22 Consistent with these observations, Pellegrini and colleagues 23 demonstrated that IL-7 treatment decreased PD-1 expression and reversed T-cell exhaustion in chronic LCMV infection. These reports imply that IL-7/IL-7R signaling in CD8 1 T cells may also affect their functions and fate in acute viral hepatitis.…”

Section: Introductionsupporting

confidence: 64%

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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Section: Introductionsupporting

confidence: 64%

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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“…The presence of CD127 on CD8+ T cells during the antiviral immune responses is thought to be a biomarker of effector T cells that successfully mature into highly proliferative protective memory T cells [33], [34]. Thus, loss of CD127 expression would be detrimental to long-term memory T cell maintenance and immune surveillance.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 Promotes Features of Replicative Senescence in Chronically Activated Human CD8+ T Cells

et al. 2014

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Prostaglandin E2 (PGE2), a pleiotropic immunomodulatory molecule, and its free radical catalyzed isoform, iso-PGE2, are frequently elevated in the context of cancer and chronic infection. Previous studies have documented the effects of PGE2 on the various CD4+ T cell functions, but little is known about its impact on cytotoxic CD8+ T lymphocytes, the immune cells responsible for eliminating virally infected and tumor cells. Here we provide the first demonstration of the dramatic effects of PGE2 on the progression of human CD8+ T cells toward replicative senescence, a terminal dysfunctional state associated multiple pathologies during aging and chronic HIV-1 infection. Our data show that exposure of chronically activated CD8+ T cells to physiological levels of PGE2 and iso-PGE2 promotes accelerated acquisition of markers of senescence, including loss of CD28 expression, increased expression of p16 cell cycle inhibitor, reduced telomerase activity, telomere shortening and diminished production of key cytotoxic and survival cytokines. Moreover, the CD8+ T cells also produced higher levels of reactive oxygen species, suggesting that the resultant oxidative stress may have further enhanced telomere loss. Interestingly, we observed that even chronic activation per se resulted in increased CD8+ T cell production of PGE2, mediated by higher COX-2 activity, thus inducing a negative feedback loop that further inhibits effector function. Collectively, our data suggest that the elevated levels of PGE2 and iso-PGE2, seen in various cancers and HIV-1 infection, may accelerate progression of CD8+ T cells towards replicative senescence in vivo. Inhibition of COX-2 activity may, therefore, provide a strategy to counteract this effect.

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“…It has been reported that after 52 weeks of telbivudine treatment, the HBeAg loss rate is approximately 26% higher than that for other nucleoside analogues . Some research suggests that telbivudine has immunoregulatory effects . Thus, patients with partial responses to pegylated interferon who switch to telbivudine may achieve a high seroconversion rate, as shown in a study from China .…”

Section: Discussionmentioning

confidence: 96%

Efficacy of sequential use of telbivudine in hepatitis B e antigen‐positive chronic hepatitis B patients with partial responses to pegylated interferon: a pilot study

Huang

Zhao

Zheng

et al. 2013

Journal of Viral Hepatitis

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The aim of this study was to investigate the efficacy of sequential use of telbivudine in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients with partial responses to pegylated interferon. Patients with partial responses to 48 weeks of pegylated interferon treatment were divided into two groups. In group A, patients stopped pegylated interferon directly without sequential treatment. In group B, patients received sequential treatment with telbivudine 600 mg/day. HBeAg, HBeAb, hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT) and creatine kinase levels were determined at baseline and at weeks 12, 24, 36 and 48. Responses and safety were assessed after 48 weeks of telbivudine treatment. Thirty-six patients were recruited. Eighteen of these patients stopped pegylated interferon without sequential treatment (group A). After 48 weeks of follow-up, five patients (28%) had undergone HBeAg seroconversion, nine patients (50%) had undetectable levels of HBV DNA, and 11 patients (61%) achieved normal alanine aminotransferase (ALT) levels. The other 18 patients received sequential telbivudine treatment (group B). After 48 weeks of treatment, 11 patients (61%) had undergone HBeAg seroconversion, and all patients had undetectable levels of HBV DNA and normal ALT levels. All patients tolerated sequential telbivudine treatment, and only slightly elevated creatine kinase levels were observed. Switching to telbivudine therapy was efficient and safe in HBeAg-positive chronic hepatitis B patients with partial responses to 48 weeks of pegylated interferon. Sequential treatment with telbivudine resulted in an HBeAg seroconversion rate of 61% and an HBV DNA loss rate of 100% after 48 weeks. This promising strategy warrants further investigation.

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Dynamic analysis of CD127 expression on memory CD8 T cells from patients with chronic hepatitis B during telbivudine treatment

Cited by 16 publications

References 18 publications

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

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

Prostaglandin E2 Promotes Features of Replicative Senescence in Chronically Activated Human CD8+ T Cells

Efficacy of sequential use of telbivudine in hepatitis B e antigen‐positive chronic hepatitis B patients with partial responses to pegylated interferon: a pilot study

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