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. 2012 Nov 20:3:346.
doi: 10.3389/fimmu.2012.00346. eCollection 2012.

CD161(+)CD4(+) T cells are enriched in the liver during chronic hepatitis and associated with co-secretion of IL-22 and IFN-γ

Yu-Hoi Kang  1 , Bianca Seigel, Bertram Bengsch, Vicki M Fleming, Eva Billerbeck, Ruth Simmons, Lucy Walker, Chris B Willberg, Eleanor J Barnes, Anisha Bhagwanani, Ye H Oo, Hubert E Blum, David H Adams, Robert Thimme, Paul Klenerman
Affiliations

CD161(+)CD4(+) T cells are enriched in the liver during chronic hepatitis and associated with co-secretion of IL-22 and IFN-γ

Yu-Hoi Kang et al. Front Immunol. .

Abstract

Hepatitis C virus infection is a major cause of chronic liver disease. CD4(+) T cells play a key role in disease outcome. However, the critical functions and associated phenotypes of intrahepatic CD4(+) T cells are not well defined. We have previously shown that CD8(+) T cells expressing the C type lectin CD161 are highly enriched in the human liver, especially during chronic hepatitis. These cells are associated with a type 17 differentiation pattern and express cytokines including IL-17A, IL-22, and IFN-γ. We therefore analyzed expression of CD161 on CD4(+) T cells in blood and liver and addressed the relevant phenotype and functional capacity of these populations. We observed marked enrichment of CD161(+)CD4(+) T cells in the liver during chronic hepatitis such that they are the dominant subtype (mean 55% of CD4(+) T cells). IL-22 and IL-17 secreting CD4(+) T cells were readily found in the livers of HCV(+) and NASH donors, although not enriched compared to blood. There was, however, specific enrichment of a novel subset of IL-22/IFN-γ dual secretors (p = 0. 02) compared to blood, a result reconfirmed with direct ex vivo analyses. These data indicate the dominance of CD161(+) expressing lymphocyte populations within the hepatic infiltrate, associated with a distinct cytokine profile VSports手机版. Given their documented roles as antiviral and hepatoprotective cytokines respectively, the impact of co-secretion of IFN-γ and IL-22 in the liver may be particularly significant. .

Keywords: CD161; CD4+ T cell; HCV; IL-22; hepatic inflammation V体育安卓版. .

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Figures

FIGURE 1
FIGURE 1
Cytokine secretion capacity of CD161+CD4+ T cells in healthy donor blood. Healthy donor blood ex vivo was stained as described in methods and analyzed for expression of the following cytokines following PMA/Ionomycin stimulation: IL-17A (A), IL-22 (B) Plots show gated live CD3+CD4+ lymphocytes. In each case an example is shown on the left and group data on the right, with comparison by Mann Whitney test.
FIGURE 2
FIGURE 2
Chemokine receptor expression of CD161+ CD4+ T cells in healthy donor blood. Healthy donor blood was stained as described in methods and analyzed for expression of the following chemokine receptors: CCR6 (A), CXCR6 (B), CXCR3 (C), and CCR2 (D). Plots show gated live CD3+CD4+ lymphocytes. In each case an example is shown on the left and group data on the right, with comparison by Mann–Whitney test.
FIGURE 3
FIGURE 3
CD161+CD4+ T cells in blood and liver in HCV infection. CD161+CD4+CD3+ T cell frequencies were examined in blood from healthy donors, HCV+ chronically infected donors and liver derived lymphocytes, studied ex vivo (A). Percentage CD161+ cells amongst CD4+ T cells in liver explants, PBMC from HCV+ donors and PBMC from healthy donors are shown. The 15 HCV+ donors studied in the analysis of PBMC were additional to those in Table 1 and comprised persistently infected donors (eight genotype 1, six genotype 3, one genotype 2), of whom five had Ishak histologic scores of 5+/6 and/or clinical cirrhosis; the IHL in this study were obtained at explant for cirrhosis from HCV+ donors. Groups were compared by Mann-Whitney tests. In (B), the phenotype of CD161+CD4+CD3+ T cells in peripheral blood of HCV+ donors and healthy controls were compared as in Figures 1 and 2. Data is shown from CXCR3 and CXCR6 analyses. No significant change was seen in analyses of CD27, CD28, CD45RA/RO, CD62L, CCR6, CD103, or PD-1.
FIGURE 4
FIGURE 4
Analysis of cytokine secreting cells in the liver of HCV+ persons and controls. (A) Liver-derived and blood-derived CD4+ and CD8+ lymphocytes were analyzed for their cytokine secretion capacity as described in methods. The fractions of cells secreting IL-17A are indicated. (B) Data for IL-22 secretion in blood and liver are indicated as for IL-17A. (C) Analysis of CD4+ T cell cytokine secretion (IFN-γ vs IL-22 and Il-17) in liver, in patients with HCV (left panel) and NASH (right panel).
FIGURE 5
FIGURE 5
Analysis of IL-22 secreting cells and polyfunctionality in blood and liver derived lymphocytes. Liver derived lymphocytes and PBMCs from HCV+ donors expanded in vitro were analyzed in parallel for expression of cytokines IL-17A, IL-22 and IFN-γ in response to PMA/Ionomycin stimulation as described in methods. In (A) an example of staining is shown. IL-22+ CD4+ T cells were gated upon and co-secretion of IL-17A and IFN-γ was assessed. In (B) the fraction of cells secreting IL-22 either alone or in combination with the other cytokines is displayed and compared (paired Student’s t-test). A significant enrichment of liver-derived IFN-γ/IL-22 co-secreting cells is observed.
FIGURE 6
FIGURE 6
Analysis of IL-22 secretion and polyfunctionality in blood and liver derived lymphocytes studied directly ex vivo. Liver derived lymphocytes and PBMCs were analyzed in parallel directly following isolation for expression of cytokines IL-17A, IL-22 and IFN-γ in response to PMA/Ionomycin stimulation. In (A) an example of staining is shown. IL-22+ CD4+ T cells were gated upon and co-secretion of IL-17A and IFN-γ was assessed. In (B) the fraction of cells secreting IL-22 either alone or in combination with the other cytokines is displayed and compared using paired Student’s t test in blood and liver. A significant enrichment of intrahepatic IL-22/IFN-γ co-secreting cells and IL-22/IFN-γ/IL-17A triple secretors is observed.
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