Regulatory T Cells in Hepatitis B and C Virus Infections

Jung, M.; Shin, Eui‐Cheol

doi:10.4110/in.2016.16.6.330

Cited by 60 publications

(69 citation statements)

References 62 publications

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“…Currently, Treg and MDSC represent two immunosuppressive cell populations that have been recognised as crucial players in the establishment of immune tolerance and in attenuation of effector cell responses, particularly in tumour microenvironment . While different studies have indicated Treg as important suppressive mediators of T‐cells during CHI, the relevance of MDSC in this disease setting and whether there exist any functional cross‐talk between MDSC and Treg remains enigmatic. A significant increase in Treg frequency had been detected in chronically HBV‐infected patients and it had been suggested that Treg could be induced through repetitive and prolonged stimulation of T‐cells by high concentrations of HBV‐antigen .…”

Section: Discussionmentioning

confidence: 99%

“…The peripheral‐induced Tregs are produced under particular conditions of antigen exposure and are subdivided into (a) FOXP3 + Treg (iTreg) and (b) FOXP3 − Treg, which includes type‐1 regulatory T‐cells (Tr1) and T‐helper type‐3 cells (Th3) that mediate suppression via interleukine‐10 (IL‐10) and transforming growth factor beta (TGF‐β)‐dependent mechanisms respectively . A marked elevation in CD4 + CD25 + FOXP3 + Treg frequency had been reported in patients with chronic hepatitis B (CHB) and had been shown to inhibit the proliferation and interferon gamma (IFN‐γ) production of HBV‐specific T‐cells and to delay the recruitment of macrophages and dendritic cells to HBV‐infected liver . Furthermore, a recent study demonstrated that Tr1‐cells suppress germinal center formation and anti‐HBV antibody production in HBV‐carrier mice .…”

Section: Introductionmentioning

confidence: 99%

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Myeloid‐derived suppressor cells induce regulatory T cells in chronically HBV infected patients with high levels of hepatitis B surface antigen and persist after antiviral therapy

Pal

Nandi

Dey

et al. 2019

Aliment Pharmacol Ther

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Summary Background CD4+ regulatory T‐cells (Tregs) expand during chronic hepatitis B virus (HBV) infection and inhibit antiviral immunity, although the underlying mechanism remains largely elusive. Myeloid‐derived suppressor cells (MDSC) have been linked with T‐cell dysfunction but questions remain regarding their persistence/profile/function in chronically HBV infected patients. Aim To characterise MDSC in different phases of chronic HBV infection namely, immune‐tolerant (IT), hepatitis B e‐antigen‐positive chronic hepatitis B (EP‐CHB), inactive carriers (IC) and hepatitis B e‐antigen‐negative chronic hepatitis B (EN‐CHB), to investigate their role in Treg induction and evaluate the effect of anti‐viral therapy on these cells. Methods Multiparametric flow cytometry, cell‐sorting and co‐culture assays were performed along with longitudinal immune monitoring of CHB patients receiving tenofovir. Results HLA‐DR‐CD11b+CD33hi‐Monocytic‐MDSC (M‐MDSC) were enhanced in IT, EP‐CHB and EN‐CHB compared with IC, and this was related to increasing hepatitis B surface antigen (HBsAg) concentration. IT and EP‐/EN‐CHB displayed elevated frequency of CD4+CD25+FOXP3+Treg that positively correlated with that of M‐MDSC. However, both M‐MDSC and HLA‐DR‐CD11b+CD33low‐granulocytic‐MDSC from IT and EP‐/EN‐CHB expressed high transforming growth factor beta (TGF‐β) and interleukin‐10 (IL‐10). Co‐culture of sorted HLA‐DR‐CD33+‐MDSC with autologous MDSC depleted‐PBMC from IT and CHB but not from IC, increased CD4+CD25+FOXP3+‐iTreg and CD4+FOXP3‐IL‐10+‐Tr1‐cells through a cell‐contact independent mechanism. While MDSC‐derived TGF‐β and IL‐10 promoted development of iTreg, only IL‐10 appeared to be crucial for Tr1 induction. One year of tenofovir treatment failed to normalise MDSC frequency/function or reduce Treg percentage and serum HBsAg levels, despite reduction in viral load. Conclusions We established a previously unrecognised role of MDSC in Treg development in IT and EP‐/EN‐CHB via TGF‐β/IL‐10‐dependent pathways and both cell‐types persisted after anti‐viral therapy. Hence, therapeutic targeting of MDSC or reducing circulating HBsAg level together with tenofovir‐therapy might be more effective in restricting HBV persistence and disease progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Myeloid‐derived suppressor cells induce regulatory T cells in chronically HBV infected patients with high levels of hepatitis B surface antigen and persist after antiviral therapy

Pal

Nandi

Dey

et al. 2019

Aliment Pharmacol Ther

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“…Therefore, in contrast to studies with NSV, IL-10 deficiency affected outcomes by a combination of increased Th1-mediated rather than Th17mediated immunopathogenesis and delayed production of antiviral antibody in the CNS, which is important for viral clearance. Many cells can produce IL-10, but regulatory T cells play a major role during viral infections of multiple organs, including the CNS (21,(32)(33)(34)(35), and are important determinants of NSV infection outcome in susceptible and resistant strains of mice (20). SINV-induced neurologic disease is a manifestation of the inflammatory response to infection rather than virus replication per se (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-10 Modulation of Virus Clearance and Disease in Mice with Alphaviral Encephalomyelitis

Martin

Griffin

2018

J Virol

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Alphaviruses are an important cause of mosquito-borne outbreaks of arthritis, rash, and encephalomyelitis. Previous studies in mice with a virulent strain (neuroadapted SINV [NSV]) of the alphavirus Sindbis virus (SINV) identified a role for Th17 cells and regulation by interleukin-10 (IL-10) in the pathogenesis of fatal encephalomyelitis (K. A. Kulcsar, V. K. Baxter, I. P. Greene, and D. E. Griffin, Proc Natl Acad Sci U S A 111:16053-16058, 2014, https://doi.org/10.1073/pnas.1418966111). To determine the role of virus virulence in generation of immune responses, we analyzed the modulatory effects of IL-10 on disease severity, virus clearance, and the CD4 T cell response to infection with a recombinant strain of SINV of intermediate virulence (TE12). The absence of IL-10 during TE12 infection led to longer morbidity, more weight loss, higher mortality, and slower viral clearance than in wild-type mice. More severe disease and impaired virus clearance in IL-10 mice were associated with more Th1 cells, fewer Th2 cells, innate lymphoid type 2 cells, regulatory cells, and B cells, and delayed production of antiviral antibody in the central nervous system (CNS) without an effect on Th17 cells. Therefore, IL-10 deficiency led to more severe disease in TE12-infected mice by increasing Th1 cells and by hampering development of the local B cell responses necessary for rapid production of antiviral antibody and virus clearance from the CNS. In addition, the shift from Th17 to Th1 responses with decreased virus virulence indicates that the effects of IL-10 deficiency on immunopathologic responses in the CNS during alphavirus infection are influenced by virus strain. Alphaviruses cause mosquito-borne outbreaks of encephalomyelitis, but determinants of outcome are incompletely understood. We analyzed the effects of the anti-inflammatory cytokine IL-10 on disease severity and virus clearance after infection with an alphavirus strain of intermediate virulence. The absence of IL-10 led to longer illness, more weight loss, more death, and slower viral clearance than in mice that produced IL-10. IL-10 influenced development of disease-causing T cells and entry into the brain of B cells producing antiviral antibody. The Th1 pathogenic cell subtype that developed in IL-10-deficient mice infected with a less virulent virus was distinct from the Th17 subtype that developed in response to a more virulent virus, indicating a role for virus strain in determining the immune response. Slow production of antibody in the nervous system led to delayed virus clearance. Therefore, both the virus strain and the host response to infection are important determinants of outcome.

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“…Regulatory T (Tregs) cells are a subset of CD4+ T cells that express the transcription factor Foxp3; they have potent immunosuppressive properties and are critically involved in transplant survival . However, the suppressive properties of Tregs can also lead to persistence of antigens and are associated with decreased clearance of chronic infections such as hepatitis B and C . Additionally, there is increasing evidence that inhibitory molecules such as PD‐1 may play a role in development of Tregs by altering the plasticity of Th1 cells, impairing cell‐mediated immunity …”

Section: Introductionmentioning

confidence: 99%

Longitudinal assessment of T cell inhibitory receptors in liver transplant recipients and their association with posttransplant infections

Mysore

Ghobrial

Kannanganat

et al. 2018

American Journal of Transplantation

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Current immunosuppression regimens in organ transplantation primarily inhibit T cells. However, T cells are also critical in protective immunity, especially in immune-compromised patients. In this study, we examined the association of T cell dysfunction, as marked by expression of T cell exhaustion molecules, and posttransplant infections in a cohort of liver transplant patients. We focused on Programmed Death 1 (PD-1) and T cell Ig- and mucin-domain molecule 3 (Tim-3), which are potent co-inhibitory receptors, and their persistent expression often leads to T cell dysfunction and compromised protective immunity. We found that patients with the highest expression of PD-1 +Tim-3+ T cells in the memory compartment before transplantation had increased incidence of infections after liver transplantation, especially within the first 90 days. Longitudinal analysis in the first year showed a strong association between variability of PD-1 and Tim-3 expression by T cells and infectious episodes in transplant patients. Furthermore, T cells that expressed PD-1 and Tim-3 had a significantly reduced capacity in producing interferon (IFN)-γ in vitro, and this reduced IFN-γ production could be partially reversed by blocking PD-1 and Tim-3. Interestingly, the percentage of Foxp3+ regulatory T cells in liver transplant patients was stable in the study period. We concluded that the functional status of T cells before and after liver transplantation, as shown by PD-1 and Tim-3 expression, may be valuable in prognosis and management of posttransplant infections.

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Regulatory T Cells in Hepatitis B and C Virus Infections

Cited by 60 publications

References 62 publications

Myeloid‐derived suppressor cells induce regulatory T cells in chronically HBV infected patients with high levels of hepatitis B surface antigen and persist after antiviral therapy

Myeloid‐derived suppressor cells induce regulatory T cells in chronically HBV infected patients with high levels of hepatitis B surface antigen and persist after antiviral therapy

Interleukin-10 Modulation of Virus Clearance and Disease in Mice with Alphaviral Encephalomyelitis

Longitudinal assessment of T cell inhibitory receptors in liver transplant recipients and their association with posttransplant infections

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