PD-1:PD-L1 Interactions Contribute to the Functional Suppression of Virus-Specific CD8+ T Lymphocytes in the Liver

Maier, Holly; Isogawa, Masanori; Freeman, Gordon J.; Chisari, Francis V.

doi:10.4049/jimmunol.178.5.2714

Cited by 214 publications

(187 citation statements)

References 47 publications

Supporting

Mentioning

172

Contrasting

Unclassified

Order By: Relevance

“…The expression levels of PD-1 were found to be high on the virus-specific T cells during persistent chronic HIV and HCV infection (19,20). In the present study, we observed a significant elevation in the expression of PD-1 on either CD4 or CD8 T cells in the pre-treatment group compared to the normal group, which was similar to the observations of recent studies on HBV (21)(22)(23)(24). Notably, the levels of PD-1 on CD8 T cells in the post-treatment group were significantly decreased compared to those in the pre-treatment group.…”

Section: A B C Discussionsupporting

confidence: 81%

Expression levels of CD28, CTLA-4, PD-1 and Tim-3 as novel indicators of T-cell immune function in patients with chronic hepatitis B virus infection

et al. 2014

View full text Add to dashboard Cite

Abstract. Chronic hepatitis B (CHB) is one of the most common types of infectious diseases worldwide. The interaction between hepatitis B virus (HBV) and the host immune response is vital for the clinical outcome of HBV infection. Costimulatory signals are key factors for the host immune response and play a critical role in innate immunity, particularly antiviral immunity. The aim of the present study was to investigate the correlation between the expression levels of costimulatory molecules and the different states of CHB infection, including the expression levels prior to and following treatment with antiviral agents. The expression levels of CD28, CTLA-4, PD-1, Tim-3 and T-cell subsets were determined by flow cytometry. The load of HBV DNA in the serum was detected by quantitative polymerase chain reaction and the serology markers, including HBeAg and alanine aminotransferase (ALT), were measured by conventional methods. Compared to the healthy control group, the expression levels of CD28 and CTLA-4 on CD4 T cells prior to and following treatment with antiviral agents (the pre-and post-treatment groups, respectively) were significantly decreased, while the expression levels of Tim-3 on CD4 and CD8 T cells were significantly increased. In addition, the expression levels of PD-1 on CD4 and CD8 T cells in the pre-treatment group were significantly increased compared to those in the post-treatment and healthy control groups. Moreover, the multivariate analysis revealed that the levels of ALT and HBV-DNA in the serum were significantly positively correlated with PD-1 expression levels. In conclusion, the expression levels of these costimulatory molecules reflect the immune dysfunction of T cells in patients with CHB and, combined with T-cell subset analysis may be used as a novel evaluation system of immune function in patients with HBV infection. IntroductionChronic hepatitis B (CHB) is one of the most common types of infectious diseases worldwide. It was previously demonstrated that hepatitis B virus (HBV) is not directly cytopathic and that the interactions between HBV and the host immune response are crucial for the clinical outcome of HBV infection (1,2). The main cause of CHB is considered to be a cell immunity function disorder. Briefly, HBV evades the cellular immune response, avoids clearance and may cause persistent viral infections. During this process, T cells play a vital role in the immune function (3). During the process of immune response, the HBV antigens are processed by antigen-presenting cells (APCs) and presented to naïve T cells by major histocompatibility complex (MHC) molecules. Subsequently, these cells deliver a primary signal to initiate T-cell activation by engaging the T-cell receptor̸CD3 complex with foreign antigens associated with MHC molecules (4). The activation of T cells is also regulated by the balance between positive and negative signals. This balance is maintained by the interaction of costimulatory or coinhibitory receptors on T cells and their ligands on APCs. These stimul...

show abstract

Section: A B C Discussionsupporting

confidence: 81%

Expression levels of CD28, CTLA-4, PD-1 and Tim-3 as novel indicators of T-cell immune function in patients with chronic hepatitis B virus infection

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The role of PD-1/B7-H1 as a mechanism for liver tolerance has been well established. Indeed, PD-1 expression by T cells has been shown to inhibit intrahepatic antiviral immune responses at the effector phase (20,21,38). The initial induction of PD-1 by CD8 ϩ T cells in both core(ϩ) and core(Ϫ) mice at the early stage of viral infection provides further evidence that PD-1 plays an important role in controlling intrahepatic T cell responses.…”

Section: Discussionmentioning

confidence: 81%

“…Furthermore, B7-H1 plays a pivotal role in the accumulation and deletion of intrahepatic CD8 ϩ T cells (19). Importantly, the PD-1/ B7-H1 inhibitory pathway has been shown to be involved in the regulation of intrahepatic T cell responses (20,21). However, it is currently not known how the PD-1/B7-H1 pathway contributes to the HCV core-mediated immune dysregulation leading to viral persistence.…”

mentioning

confidence: 99%

Blockade of PD-1/B7-H1 Interaction Restores Effector CD8+ T Cell Responses in a Hepatitis C Virus Core Murine Model

Lukens

Cruise

Lassen

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

The impaired function of CD8+ T cells is characteristic of hepatitis C virus (HCV) persistent infection. HCV core protein has been reported to inhibit CD8+ T cell responses. To determine the mechanism of the HCV core in suppressing Ag-specific CD8+ T cell responses, we generated a transgenic mouse, core(+) mice, where the expression of core protein is directed to the liver using the albumin promoter. Using a recombinant adenovirus to deliver Ag, we demonstrated that core(+) mice failed to clear adenovirus-LacZ (Ad-LacZ) infection in the liver. The effector function of LacZ-specific CD8+ T cells was particularly impaired in the livers of core(+) mice, with suppression of IFN-γ, TNF-α, and granzyme B production by CD8+ T cells. In addition, the impaired CD8+ T cell responses in core(+) mice were accompanied by the enhanced expression of the inhibitory receptor programmed death-1 (PD-1) by LacZ-specific CD8+ T cells and its ligand B7-H1 on liver dendritic cells following Ad-LacZ infection. Importantly, blockade of the PD-1/B7-H1 inhibitory pathway (using a B7-H1 blocking antibody) in core(+) mice enhanced effector function of CD8+ T cells and cleared Ad-LacZ-infection as compared with that in mice treated with control Ab. This suggests that the regulation of the PD-1/B7-H1 inhibitory pathway is crucial for HCV core-mediated impaired T cell responses and viral persistence in the liver. This also suggests that manipulation of the PD-1/B7-H1 pathway may be a potential immunotherapy to enhance effector T cell responses during persistent HCV infection.

show abstract

“…119 However, there are also data suggesting that most intrahepatic CD8 ϩ T cells are toleragenic and express PD-1. 120 One of the evasion mechanisms used by HCV to escape immune responses, especially CD8 responses, is the development of viral escape mutants. 121 Finally, a significant correlation has been demonstrated between the number of lobular CD8 ϩ T cells and ALT levels, suggesting a prominent role for T cell-mediated cytotoxicity in the genesis of hepatocellular damage.…”

Section: Role Of Cd8 T Cellsmentioning

confidence: 99%

Acute hepatitis C virus infection: A chronic problem

et al. 2007

View full text Add to dashboard Cite

S ince the discovery of the hepatitis C virus (HCV) in the late 1980s, there has been an explosion of information regarding its natural history, treatment, and replication cycle. Nonetheless, there are still relatively few data regarding acute HCV infection. By convention, the term acute hepatitis refers to the presence of clinical signs or symptoms of hepatitis for a period of 6 months or fewer after the presumed time of HCV exposure. Early studies of posttransfusion patients who developed non-A, non-B hepatitis provide a clinical picture of early infection. 1 Following the availability of specific serologic and virologic tests, most such patients were shown to have acute HCV infection. After acute infection, HCV RNA may become detectable in the serum/plasma in as little as 2 weeks ( Fig. 1). Several weeks later, a high percentage of patients experience an increase in serum aminotransferase levels consistent with the development of acute hepatocellular injury. In the majority of cases, patients develop mild constitutional symptoms, including abdominal pain, nausea, vomiting, anorexia, and fatigue. During this acute infection, serum aminotransferases often peak below 1000 IU/mL and may return to normal levels. A minority develops sufficient elevations in bilirubin to lead to overt jaundice or the development of dark urine. Unless the clinical suspicion is high, few patients will be tested for HCV RNA or HCV antibody seroconversion. However, in the majority-but not all-of infected patients, HCV RNA persists, and a chronic disease state develops.The reasons for the general lack of data regarding acute HCV infection are multifactorial and include (1) the relatively high percentage of asymptomatic or unrecognized early infections, (2) the lack of large-scale identification of chronic carriers in the general population who serve as a reservoir for infection, and (3) the decreased number of acute infections that occur in controlled clinical settings such as that of blood transfusions. These factors and the lack of nonprimate animal models necessitate reliance on retrospective studies in chronic carriers, the use of limited historical collections of banked sera, and the extrapolation of outcomes based on small disease outbreaks in unique settings (for example, transmission from a physician to a patient in the operating room setting or following parenteral exposure in healthcare workers). Moreover, there exist only a limited number of population cohorts that continue to experience high rates of HCV transmission (for example, Egypt); nonetheless, there is a growing body of information regarding the clinical presentation, natural history, and treatment outcomes of acute HCV infection.In this article, we review the current information regarding our understanding of the epidemiology, virology, and immunology of HCV with a particular emphasis on acute HCV infection. In addition, we review recent data related to interferon-based treatment intervention and propose an algorithm for the diagnosis and management of acute HCV inf...

show abstract

PD-1:PD-L1 Interactions Contribute to the Functional Suppression of Virus-Specific CD8+ T Lymphocytes in the Liver

Cited by 214 publications

References 47 publications

Expression levels of CD28, CTLA-4, PD-1 and Tim-3 as novel indicators of T-cell immune function in patients with chronic hepatitis B virus infection

Expression levels of CD28, CTLA-4, PD-1 and Tim-3 as novel indicators of T-cell immune function in patients with chronic hepatitis B virus infection

Blockade of PD-1/B7-H1 Interaction Restores Effector CD8+ T Cell Responses in a Hepatitis C Virus Core Murine Model

Acute hepatitis C virus infection: A chronic problem

Contact Info

Product

Resources

About