Immunization with hepatitis C virus core gene triggers potent T-cell response, but affects CD4+ T-cells

Regulatory T cell markers are increased in chronically infected individuals with the hepatitis C virus (HCV), but to date, the induction and maintenance of Tregs in HCV infection has not been clearly defined. In this paper, we demonstrate that naturally occurring viral variants suppress T cell responses to cognate NS3358-375in an antigen-specific manner. Of four archetypal variants, S370P induced regulatory T cell markers in comparison to NS3358-375-stimulated CD4 T cells. Further, the addition of variant-specific CD4 T cells back into a polyclonal culture in a dose-dependent manner inhibited the T cell response. These results suggest that HCV is able to induce antigen-specific regulatory T cells to suppress the antiviral T cell response in an antigen-specific manner, thus contributing to a niche within the host that could be conducive to HCV persistence.

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Strain-Specific T-Cell Suppression and Protective Immunity in Patients with Chronic Hepatitis C Virus Infection

Journal of Virology ◽

10.1128/jvi.79.11.6976-6983.2005 ◽

2005 ◽

Vol 79 (11) ◽

pp. 6976-6983 ◽

Cited By ~ 35

Author(s):

Kazushi Sugimoto ◽

David E. Kaplan ◽

Fusao Ikeda ◽

Jin Ding ◽

Jonathan Schwartz ◽

...

Keyword(s):

T Cells ◽

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Cell Response ◽

T Cell Responses ◽

T Cell Response ◽

Cd4 T Cell ◽

Cell Responses ◽

Genotype 2

ABSTRACT Hepatitis C virus (HCV) frequently persists with an apparently ineffective antiviral T-cell response. We hypothesized that some patients may be exposed to multiple HCV subtypes and that strain-specific T cells could contribute to the viral dynamics in this setting. To test this hypothesis, CD4 T-cell responses to three genotype 1a-derived HCV antigens and HCV antibody serotype were examined in chronically HCV infected (genotypes 1a, 1b, 2, 3, and 4) and spontaneously HCV recovered subjects. Consistent with multiple HCV exposure, 63% of patients infected with genotypes 2 to 4 (genotypes 2-4) and 36% of those infected with genotype 1b displayed CD4 T-cell responses to 1a-derived HCV antigens, while 29% of genotype 2-4-infected patients showed serotype responses to genotype 1. Detection of 1a-specific T cells in patients without active 1a infection suggested prior self-limited 1a infection with T-cell-mediated protection from 1a but not from non-1a viruses. Remarkably, CD4 T-cell responses to 1a-derived HCV antigens were weakest in patients with homologous 1a infection and greater in non-1a-infected patients: proportions of patients responding were 19% (1a), 36% (1b), and 63% (2-4) (P = 0.0006). Increased 1a-specific CD4 T-cell responsiveness in non-1a-infected patients was not due to increased immunogenicity or cross-reactivity of non-1a viruses but directly related to sequence divergence. We conclude that the T-cell response to the circulating virus is either suppressed or not induced in a strain-specific manner in chronically HCV infected patients and that, despite their ability to clear one HCV strain, patients may be reinfected with a heterologous strain that can then persist. These findings provide new insights into host-virus interactions in HCV infection that have implications for vaccine development.

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MOG extracellular domain (p1–125) triggers elevated frequency of CXCR3+ CD4+ Th1 cells in the CNS of mice and induces greater incidence of severe EAE

Multiple Sclerosis Journal ◽

10.1177/1352458514524086 ◽

2014 ◽

Vol 20 (10) ◽

pp. 1312-1321 ◽

Cited By ~ 5

Author(s):

Jyothi T Mony ◽

Reza Khorooshi ◽

Trevor Owens

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Cd4 T Cells ◽

Cd8 T Cell ◽

Interferon Γ ◽

T Cell Response ◽

Receptor Expression ◽

Myelin Proteins ◽

Mhc Ii

Background: Myelin-specific T cells are implicated in multiple sclerosis (MS) and drive experimental autoimmune encephalomyelitis (EAE). EAE is commonly induced with short peptides, whereas in MS, whole myelin proteins are available for immune response. We asked whether immunization with the immunoglobulin-like domain of myelin oligodendrocyte glycoprotein (MOGIgd, residues 1–125) might induce distinct CD4+ T-cell response and/or a stronger CD8+ T-cell response, compared to the 21 amino acid immunodominant MHC II-associating peptide (p35–55). Objectives: Compare both EAE and T-cell responses in C57BL/6 mice immunized with MOGIgd and MOG p35–55. Methods: Cytokine production, and chemokine receptor expression by CD4+ and CD8+ T cells in the mouse central nervous system (CNS), were analyzed by flow cytometry. Results: MOGIgd triggered progression to more severe EAE than MOG p35–55, despite similar time of onset and overall incidence. EAE in MOGIgd-immunized mice was characterized by an increased percentage of CXCR3+ interferon-γ-producing CD4+ T cells in CNS. The CD8+ T-cell response to both immunogens was similar. Conclusions: Increased incidence of severe disease following MOGIgd immunization, accompanied by an increased percentage of CD4+ T cells in the CNS expressing CXCR3 and producing interferon-γ, identifies a pathogenic role for interferon-γ that is not seen when disease is induced with a single Major Histocompatibility Complex (MHC) II-associating epitope.

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Role of the specific T‐cell response for clearance and control of hepatitis C virus

Journal of Viral Hepatitis ◽

10.1046/j.1365-2893.1999.00006.x ◽

1999 ◽

Vol 6 (s1) ◽

pp. 36-40 ◽

Cited By ~ 75

Author(s):

G. R. Pape ◽

T. J. Gerlach ◽

H. M. Diepolder ◽

N. Grüner ◽

M.‐C. Jung ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

And Control

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447 Reinfection with the hepatitis C virus: Kinetics of viral clearance and multi-parameter analysis of CD4+ T-cell response

Journal of Hepatology ◽

10.1016/s0168-8278(06)80447-2 ◽

2006 ◽

Vol 44 ◽

pp. S167 ◽

Cited By ~ 1

Author(s):

L. Weseslindtner ◽

J.H. Aberle ◽

C. Gurguta ◽

P. Steindl-Munda ◽

T. Popow-Kraupp ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

Viral Clearance ◽

Parameter Analysis ◽

Cd4 T Cell ◽

Kinetics Of

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CD4+ T cells specific for glycoprotein B from cytomegalovirus exhibit extreme conservation of T-cell receptor usage between different individuals

Blood ◽

10.1182/blood-2007-04-079863 ◽

2008 ◽

Vol 111 (4) ◽

pp. 2053-2061 ◽

Cited By ~ 25

Author(s):

Laura Crompton ◽

Naeem Khan ◽

Rajiv Khanna ◽

Laxman Nayak ◽

Paul A. H. Moss

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Response ◽

Cd4 T Cells ◽

Clonal Selection ◽

Cell Receptor ◽

T Cell Response ◽

Cd4 T Cell ◽

Extreme Conservation

Antigen-specific CD8+ cytotoxic T cells often demonstrate extreme conservation of T-cell receptor (TCR) usage between different individuals, but similar characteristics have not been documented for CD4+ T cells. CD4+ T cells predominantly have a helper immune role, but a cytotoxic CD4+ T-cell subset has been characterized, and we have studied the cytotoxic CD4+ T-cell response to a peptide from human cytomegalovirus glycoprotein B presented through HLA-DRB*0701. We show that this peptide elicits a cytotoxic CD4+ T-cell response that averages 3.6% of the total CD4+ T-cell repertoire of cytomegalovirus-seropositive donors. Moreover, CD4+ cytotoxic T-cell clones isolated from different individuals exhibit extensive conservation of TCR usage, which indicates strong T-cell clonal selection for peptide recognition. Remarkably, this TCR sequence was recently reported in more than 50% of cases of CD4+ T-cell large granular lymphocytosis. Immunodominance of cytotoxic CD4+ T cells thus parallels that of CD8+ subsets and suggests that cytotoxic effector function is critical to the development of T-cell clonal selection, possibly from immune competition secondary to lysis of antigen-presenting cells. In addition, these TCR sequences are highly homologous to those observed in HLA-DR7+ patients with CD4+ T-cell large granular lymphocytosis and implicate cytomegalovirus as a likely antigenic stimulus for this disorder.

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Induction of cytotoxic T-cell response against hepatitis C virus structural antigens using a defective recombinant adenovirus

Hepatology ◽

10.1002/hep.510250236 ◽

1997 ◽

Vol 25 (2) ◽

pp. 470-477 ◽

Cited By ~ 52

Author(s):

O Bruña-Romero ◽

J J Lasarte ◽

G Wilkinson ◽

K Grace ◽

B Clarke ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Cell Response ◽

Recombinant Adenovirus ◽

T Cell Response ◽

Cytotoxic T Cell

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Loss of EBV-Specific CD4+T Cells during Progression to EBV-Related AIDS Non-Hodgkin Lymphoma: Restoration by Highly Active Antiretroviral Therapy (HAART).

Blood ◽

10.1182/blood.v104.11.3110.3110 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3110-3110

Author(s):

Erwan R. Piriou ◽

Christine Jansen ◽

Karel van Dort ◽

Iris De Cuyper ◽

Nening M. Nanlohy ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Cd4 T Cells ◽

Antigen Processing ◽

Ex Vivo ◽

T Cell Response ◽

Cd4 T Cell ◽

Cell Numbers

Abstract Objective: EBV-specific CD8+ T cells have been extensively studied in various settings, and appear to play a major role in the control of EBV-related malignancies. In contrast, it is still unclear whether EBV-specific CD4+ T cells play a role in vivo. To study this question, an assay was developed to measure the CD4+ T-cell response towards two EBV antigens, in both healthy (n=14) and HIV-infected subjects (n=23). In addition, both HAART-treated (n=12) and untreated HIV+ individuals (n=14) - including progressors to EBV-related lymphoma - were studied longitudinally. Methods: EBV-specific CD4+ T cells were stimulated with peptide pools from latent protein EBNA1 and lytic protein BZLF1, and detected by measurement of IFNg-production. Results: After direct ex vivo stimulation, EBNA1 or BZLF1-specific IFNg- (and/or IL2) producing CD4+ T cell numbers were low, and measurable in less than half of the subjects studied (either HIV- and HIV+). Therefore, PBMC were cultured for 12 days in the presence of peptides and IL2 (from day 3), and then restimulated with peptides, allowing specific and reproducible expansion of EBV-specific CD4+ T cells, independent of HLA type and ex vivo antigen processing. Interestingly, numbers of EBV-specific CD4+ T cells inversely correlated with EBV viral load, implying an important role for EBV-specific CD4+ T cells in the control of EBV in vivo. Untreated HIV-infected individuals had a lower CD4+ T cell response to EBNA1 and BZLF1 as compared to healthy EBV carriers and HAART-treated HIV+ subjects. In longitudinal samples, EBNA1-specific, but not BZLF1-specific T-cell numbers increased after HAART, while EBV load was not affected by treatment. In all the progressors to EBV-related lymphoma, EBV-specific CD4+ T cells were lost at least 24 months before lymphoma diagnosis. Conclusions: Both cross-sectional and longitudinal data suggest an important role for EBV-specific CD4+ T cells in the control of EBV-related malignancies. Furthermore, it seems that HAART treatment leads to recovery of EBNA1-specific, but not BZLF1-specific CD4+ T-cell responses, implying changes in the latency pattern of EBV, despite an unaltered cell-associated EBV DNA load. Thus, early HAART treatment might prevent loss of specific CD4+ T-cell help and progression to NHL.

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