Increased Frequencies of Circulating IFN-γ-Producing Vδ1+ and Vδ2+ γδ T Cells in Patients with Asymptomatic Persistent Hepatitis B Virus Infection
To cite this article:
Conroy Melissa J., Mac Nicholas Ross, Taylor Margaret, O'Dea Siobhan, Mulcahy Fiona, Norris Suzanne, and Doherty Derek G.. Viral Immunology. May 2015, 28(4): 201-208. doi:10.1089/vim.2014.0133.
Published in Volume: 28 Issue 4: May 7, 2015
Online Ahead of Print: March 19, 2015
Author information
Melissa J. Conroy,1,2,3 Ross Mac Nicholas,4 Margaret Taylor,4 Siobhan O'Dea,5 Fiona Mulcahy,5 Suzanne Norris,4 and Derek G. Doherty1,2
1Department of Immunology, School of Medicine, Trinity College, Dublin, Ireland.
2Department of Surgery, School of Medicine, Trinity College, Dublin, Ireland.
3Institute of Immunology, National University of Ireland, Maynooth, Co. Kildare, Ireland.
4Hepatology Centre, St. James's Hospital, Dublin, Ireland.
5Genitourinary and Infectious Diseases Clinic, St. James's Hospital, Dublin, Ireland.
Address correspondence to:
Dr. Derek G. Doherty
Department of Immunology, School of Medicine
Trinity College Dublin
St. James's Hospital
Dublin 8
Ireland
E-mail: [email protected]
ABSTRACT
Hepatitis B virus (HBV) is a leading cause of liver cirrhosis and hepatocellular carcinoma. The outcome of HBV infection is largely determined by the host immune response, with virus-specific cytotoxic T cells being able to mediate immunity against HBV as well as causing liver pathology. γδ T cells are reported to be depleted in patients with HBV-associated liver disease. However, it is not known if these cells control HBV infection in patients with asymptomatic chronic HBV infection. In this study, the frequencies, phenotypes, and interferon-γ production were examined by circulating γδ T cell subsets in a group of asymptomatic HBV carriers with low viral loads and little evidence of liver disease. It is shown that γδ T cells expressing Vδ1 and Vδ2 T cell receptors and effector-memory phenotypes are found at higher frequencies in these patients compared to controls. Vδ2 T cells from the patients expressed interferon-γ significantly more frequently than Vδ2 T cells from healthy donors in the absence of ex vivo stimulation. These data suggest that effector-memory IFN-γ-producing Vδ2 T cells may contribute to the control of HBV in patients with asymptomatic infection, without mediating liver pathology. 作者: StephenW 时间: 2015-5-20 22:41
Hepatitis B virus (HBV) remains a major global health problem and is attributable to 780,000 deaths each year, despite the availability of a vaccine (58). More than 240 million people worldwide have chronic HBV infection, which can lead to cirrhosis, hepatocellular carcinoma (HCC), and liver failure (30,47). While the majority of adult HBV infections resolve, 80–90% of infected neonates develop chronic infection and 15–25% die from HBV-related liver disease or cancer (58). The majority of patients with chronic HBV infection do not develop liver disease and are said to be asymptomatic carriers. However, as many as 20% of patients in the immune control phase of chronic HBV infection develop reactivation of the virus and cirrhosis within 5 years (25,43,46). Therefore, although a vaccine exists with 95% efficacy, new treatments are urgently required to treat the vast numbers of HBV-infected patients worldwide who are at risk of HBV-related liver cirrhosis and cancer (58).
Resolution of HBV infection is associated with strong, polyclonal, and multi-specific CD8+ cytotoxic T-lymphocyte (CTL) responses directed against multiple viral epitopes, while chronic HBV infection is characterized by lower numbers and lower potency of HBV-specific CTLs (38,43,46,55). Inefficient T cell priming by dendritic cells (21,40), immunomodulation by regulatory T cells (28,54), and clonal exhaustion due to upregulation of inhibitory receptors, such as PD-1 (27,59), have been implicated as factors that contribute to the inadequate T cell responses. Moreover, CD8+ CTL-mediated cytotoxicity is strongly implicated in HBV-related liver damage but does not appear to play a major role in eliminating the virus, while IFN-γ produced by virus-specific CTLs and natural killer (NK) cells are thought to mediate clearance of HBV by interfering with viral replication and by recruiting other antigen-nonspecific effector cells (13,31,36,38,55). Therefore, the ideal immune response against HBV must control viral replication but limit hepatocyte cytotoxicity and immune-mediated liver damage.
Roles for γδ T cells in antiviral immune responses have been reported for cytomegalovirus (17,32), Epstein–Barr virus (18), human immunodeficiency virus (HIV) (45), and herpes simplex virus (39) infections. γδ T cells have also been implicated in immune responses to hepatitis C virus (HCV) and are thought to play a role in liver injury associated with the virus (41,56). Sing et al. (50) reported that γδ T cells were expanded in the blood of patients with HBV infection who seroconverted. Subsequently, Chen et al. (10,11) reported that Vδ2 T cells, the most abundant subset of γδ T cells in human blood and liver (37), are depleted in patients with chronic HBV infection and in patients who develop HBV-associated acute-on-chronic liver failure (HBV-ACLF). In contrast, Vδ1 T cells, the most abundant γδ T cell subset in the intestine, were expanded in the blood of patients with HBV-ACLF. γδ from HBV-ACLF patients exhibited enhanced cytotoxicity and inflammatory cytokine production compared to their counterparts in chronic HBV patients and healthy controls, suggesting that γδ T cells play a role in liver injury in HBV-ACLF (10).
In the present study, the potential role of γδ T cell subsets in immunity against HBV in the absence of liver injury was investigated by studying a cohort of patients with persistent HBV infection (HBsAg-positive) but low viral burden (<20,000 copies/mL) and no evidence of liver disease (alanine aminotransferase [ALT] <70 IU/mL). This patient cohort can be considered as having an efficient immune response against HBV, which is under sufficient regulatory control and does not cause significant pathology but fails to eliminate the virus completely (34). The frequencies, differentiation status, and IFN-γ production of the Vδ1+ and Vδ2+ subsets of γδ T cells were examined to assess, for the first time, their potential roles in controlled asymptomatic HBV infection.作者: StephenW 时间: 2015-5-20 22:44
在本研究中，γδT细胞亚群在免疫抗HBV在无肝损伤的潜在作用通过研究例持续HBV感染（HBsAg阳性），但低病毒负荷（<20,000份队列/ mL的调查），并没有任何证据肝病（丙氨酸氨基转移酶[ALT] <70 IU / mL）中。这个病人队列可以被看作是具有抗HBV的有效的免疫反应，这是在充分的监管控制和不会引起显著病理学，但无法完全消除病毒（34）。频率，分化状态，和IFN-γ生产的Vδ1+和Vδ2+亚群γδT细胞进行了检查，以评估，对于第一次，其在受控无症状HBV感染的潜在作用。作者: StephenW 时间: 2015-5-20 22:45
Discussion
Vδ2 T cells are the predominant γδ T cell subset in human blood and are capable of producing IFN-γ and TNF-α (23,24), killing target cells (3,22,23), inducing activation and maturation of neutrophils (15,16), monocytes (24), B-cells (7,9), and dendritic cells (14,23,35), and presenting antigen to conventional CD4+ and CD8+ T cells (8). Their multifunctional capacity makes them ideal candidates for immunotherapy, and they are already the focus of several clinical trials (5,12,20,42,51). Vδ1 T cells are mainly found at mucosal surfaces and can exhibit immunostimulatory (26,29) and immunoregulatory (6) functions and are also under consideration as therapeutic targets (49).
Previous studies have revealed that Vδ2 T cell frequencies are decreased in the peripheral blood of chronic HBV patients with liver disease (11) and with HBV-ACLF (10), whereas Vδ1 T cells are expanded in the blood of HBV-ACLF patients and exhibit enhanced cytotoxicity and cytokine production compared to Vδ1 T cells from healthy controls. A cohort of asymptomatic, HBeAg-negative patients with persistent HBV infection with little evidence of liver disease was studied to provide an insight into the possible roles of γδ T cells in the immune control of HBV infection without significant liver injury. IFN-γ-producing Vδ1 and Vδ2 T cells with effector memory phenotypes are found at higher frequencies in the peripheral blood of these patients compared to controls. This suggests that these γδ T cell subsets are expanded in the circulation of patients, although the possibility that their increased frequencies are the result of a contraction of other T cell subsets cannot be excluded. Future studies are required to determine if Vδ1 and Vδ2 T cells are also expanded in the patients' livers. However, one study (44) has demonstrated that the numbers of peripheral and intrahepatic lymphocyte subtypes correlate closely with each other. Therefore, it is likely that effector memory Vδ1 and Vδ2 T cells may contribute to the immune control of HBV infection without causing liver pathology. The finding in the present study contrasts with the depletions of these cells in patients with HBV-associated liver disease and HBV-ACLF (10,11), which may facilitate liver damage. A role for Vδ2 T cells in immunity against HCV was reported by Agrati et al. (1), while the same group has provided evidence that Vδ1 T cells contribute to liver damage in patients with HCV infection (2).
As well as being expanded, the present study has revealed that greater proportions of Vδ1 and Vδ2 T cells from asymptomatic HBV patients displayed effector memory phenotypes compared to Vδ1 and Vδ2 T cells from uninfected control subjects, while the proportions of naïve Vδ1 and Vδ2 T cells were substantially lower. This suggests that Vδ1 and Vδ2 T cells are actively involved in immunity against HBV. Previous studies have shown that circulating HBV-specific CD8+ T cells from patients with acute HBV infection predominantly express memory T cell phenotypes, suggesting that they are also actively involved in immunity against HBV (52,57). It was also found that in the absence of ex vivo stimulation, the frequencies of IFN-γ-expressing Vδ2 T cells were higher in the HBV-infected patients compared to healthy controls. This suggests that Vδ2 T cells may control HBV infection and prevent immune-mediated damage by a mechanism that involves IFN-γ-mediated viral clearance. A similar role for subsets of NK cells in IFN-γ-mediated control of HBV without liver-damaging cytotoxicity has been proposed (13,48,60). The elevated frequencies of circulating Vδ1 T cells with effector memory phenotypes, although not as significant as those observed for Vδ2 T cells, suggest that these cells also play a role in the antiviral immune response against HBV, possibly via the production of IFN-γ and TNF-α (52). Since Vδ1 T cells have previously been implicated in the pathogenesis of HCV infection and arthritis, they might require strict regulation in asymptomatic HBV infection (2,4). However, they have also previously been shown to regulate inflammatory responses of CD8+ T cells in the small intestine via the suppression of IFN-γ, granzyme-B, and NKG2D expression (6). Further work is required to determine whether this γδ T cell subset plays a predominant antiviral or regulatory role in the control of HBV infection. 作者: StephenW 时间: 2015-5-20 22:46