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HCV+ hepatocytes induce human regulatory CD4+ T cells through the production of TGF-beta.

Hall CH, Kassel R, Tacke RS, Hahn YS - PLoS ONE (2010)

Bottom Line: Hepatitis C Virus (HCV) is remarkably efficient at establishing persistent infection and is associated with the development of chronic liver disease.Notably, CD4(+) T cells in contact with Huh7.5-FL expressed an increased level of the Treg markers, CD25, Foxp3, CTLA-4 and LAP, and were able to suppress the proliferation of effector T cells.These results demonstrate that HCV infected hepatocytes are capable of directly inducing Tregs development and may contribute to impaired host T cell responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA.

ABSTRACT

Background: Hepatitis C Virus (HCV) is remarkably efficient at establishing persistent infection and is associated with the development of chronic liver disease. Impaired T cell responses facilitate and maintain persistent HCV infection. Importantly, CD4(+) regulatory T cells (Tregs) act by dampening antiviral T cell responses in HCV infection. The mechanism for induction and/or expansion of Tregs in HCV is unknown.

Methodology/principal findings: HCV-expressing hepatocytes were used to determine if hepatocytes are able to induce Tregs. The infected liver environment was modeled by establishing the co-culture of the human hepatoma cell line, Huh7.5, containing the full-length genome of HCV genotype 1a (Huh7.5-FL) with activated CD4(+) T cells. The production of IFN-gamma was diminished following co-culture with Huh7.5-FL as compared to controls. Notably, CD4(+) T cells in contact with Huh7.5-FL expressed an increased level of the Treg markers, CD25, Foxp3, CTLA-4 and LAP, and were able to suppress the proliferation of effector T cells. Importantly, HCV(+) hepatocytes upregulated the production of TGF-beta and blockade of TGF-beta abrogated Treg phenotype and function.

Conclusions/significance: These results demonstrate that HCV infected hepatocytes are capable of directly inducing Tregs development and may contribute to impaired host T cell responses.

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Related in: MedlinePlus

TGF-β contributes to increased regulatory T cell development.TGF-β blocking antibody (0.1 µg/mL) was added to the co-culture in order to monitor impairment of Treg development by (A, B) percentage developing a Treg phenotype or (C) IFN-γ production within the co-cultures. Percent suppression is calculated as ((Huh7.5-Huh7.5-FL)/Huh7.5)*100. Data are compiled from 7 CD4+ T cell donors.
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pone-0012154-g005: TGF-β contributes to increased regulatory T cell development.TGF-β blocking antibody (0.1 µg/mL) was added to the co-culture in order to monitor impairment of Treg development by (A, B) percentage developing a Treg phenotype or (C) IFN-γ production within the co-cultures. Percent suppression is calculated as ((Huh7.5-Huh7.5-FL)/Huh7.5)*100. Data are compiled from 7 CD4+ T cell donors.

Mentions: TGF-β is known to be a potent inducer of Foxp3 expression and Treg development [9]. Therefore, we examined the ability of a TGF-β blockade to prevent Treg induction in hepatocyte co-culture. As demonstrated in Fig. 5A and 5B, blockade of TGF-β activity resulted in decreased expression of Foxp3. We next evaluated if blockade of TGF-β resulted in recovery of the antiviral response by assessing IFN-γ production in the presence of TGF-β blocking antibody. TGF-β blockade resulted in a partial recovery of IFN-γ production in 6 out of 7 CD4 donors (Fig. 5C).


HCV+ hepatocytes induce human regulatory CD4+ T cells through the production of TGF-beta.

Hall CH, Kassel R, Tacke RS, Hahn YS - PLoS ONE (2010)

TGF-β contributes to increased regulatory T cell development.TGF-β blocking antibody (0.1 µg/mL) was added to the co-culture in order to monitor impairment of Treg development by (A, B) percentage developing a Treg phenotype or (C) IFN-γ production within the co-cultures. Percent suppression is calculated as ((Huh7.5-Huh7.5-FL)/Huh7.5)*100. Data are compiled from 7 CD4+ T cell donors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2921368&req=5

pone-0012154-g005: TGF-β contributes to increased regulatory T cell development.TGF-β blocking antibody (0.1 µg/mL) was added to the co-culture in order to monitor impairment of Treg development by (A, B) percentage developing a Treg phenotype or (C) IFN-γ production within the co-cultures. Percent suppression is calculated as ((Huh7.5-Huh7.5-FL)/Huh7.5)*100. Data are compiled from 7 CD4+ T cell donors.
Mentions: TGF-β is known to be a potent inducer of Foxp3 expression and Treg development [9]. Therefore, we examined the ability of a TGF-β blockade to prevent Treg induction in hepatocyte co-culture. As demonstrated in Fig. 5A and 5B, blockade of TGF-β activity resulted in decreased expression of Foxp3. We next evaluated if blockade of TGF-β resulted in recovery of the antiviral response by assessing IFN-γ production in the presence of TGF-β blocking antibody. TGF-β blockade resulted in a partial recovery of IFN-γ production in 6 out of 7 CD4 donors (Fig. 5C).

Bottom Line: Hepatitis C Virus (HCV) is remarkably efficient at establishing persistent infection and is associated with the development of chronic liver disease.Notably, CD4(+) T cells in contact with Huh7.5-FL expressed an increased level of the Treg markers, CD25, Foxp3, CTLA-4 and LAP, and were able to suppress the proliferation of effector T cells.These results demonstrate that HCV infected hepatocytes are capable of directly inducing Tregs development and may contribute to impaired host T cell responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA.

ABSTRACT

Background: Hepatitis C Virus (HCV) is remarkably efficient at establishing persistent infection and is associated with the development of chronic liver disease. Impaired T cell responses facilitate and maintain persistent HCV infection. Importantly, CD4(+) regulatory T cells (Tregs) act by dampening antiviral T cell responses in HCV infection. The mechanism for induction and/or expansion of Tregs in HCV is unknown.

Methodology/principal findings: HCV-expressing hepatocytes were used to determine if hepatocytes are able to induce Tregs. The infected liver environment was modeled by establishing the co-culture of the human hepatoma cell line, Huh7.5, containing the full-length genome of HCV genotype 1a (Huh7.5-FL) with activated CD4(+) T cells. The production of IFN-gamma was diminished following co-culture with Huh7.5-FL as compared to controls. Notably, CD4(+) T cells in contact with Huh7.5-FL expressed an increased level of the Treg markers, CD25, Foxp3, CTLA-4 and LAP, and were able to suppress the proliferation of effector T cells. Importantly, HCV(+) hepatocytes upregulated the production of TGF-beta and blockade of TGF-beta abrogated Treg phenotype and function.

Conclusions/significance: These results demonstrate that HCV infected hepatocytes are capable of directly inducing Tregs development and may contribute to impaired host T cell responses.

Show MeSH
Related in: MedlinePlus