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Follicular helper T cells promote liver pathology in mice during Schistosoma japonicum infection.

Chen X, Yang X, Li Y, Zhu J, Zhou S, Xu Z, He L, Xue X, Zhang W, Dong X, Wu H, Li CJ, Hsu HT, Kong W, Liu F, Tripathi PB, Yu MS, Chang J, Zhou L, Su C - PLoS Pathog. (2014)

Bottom Line: Following Schistosoma japonicum (S. japonicum) infection, granulomatous responses are induced by parasite eggs trapped in host organs, particular in the liver, during the acute stage of disease.While excessive liver granulomatous responses can lead to more severe fibrosis and circulatory impairment in chronically infected host.In addition, our results showed that the generation of Tfh cells driven by macrophages is dependent on cell-cell contact and the level of inducible costimulator ligand (ICOSL) on macrophages which is regulated by CD40-CD40L signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathogen Biology & Immunology, Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, P. R. China.

ABSTRACT
Following Schistosoma japonicum (S. japonicum) infection, granulomatous responses are induced by parasite eggs trapped in host organs, particular in the liver, during the acute stage of disease. While excessive liver granulomatous responses can lead to more severe fibrosis and circulatory impairment in chronically infected host. However, the exact mechanism of hepatic granuloma formation has remained obscure. In this study, we for the first time showed that follicular helper T (Tfh) cells are recruited to the liver to upregulate hepatic granuloma formation and liver injury in S. japonicum-infected mice, and identified a novel function of macrophages in Tfh cell induction. In addition, our results showed that the generation of Tfh cells driven by macrophages is dependent on cell-cell contact and the level of inducible costimulator ligand (ICOSL) on macrophages which is regulated by CD40-CD40L signaling. Our findings uncovered a previously unappreciated role for Tfh cells in liver pathology caused by S. japonicum infection in mice.

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Macrophages drive Tfh cell generation.Expression of CXCR5 versus PD-1 on CD4+ T cells (gated as CD3+CD4+) after co-culture of normal mice derived CD4+ T cells with macrophages (A, B), B cells (E, F), and DCs (G, H) from normal or infected mice in the presence or absence of SEA. Numbers represent the frequency of the boxed population within the CD4+ T cell population; (C) Quantitative RT-PCR analysis of the expression of BCL-6 mRNA in CD4+ T cells cultured with or without macrophage from infected mice. ***, P<0.001; **, P<0.01; *, P<0.05 (Student's t-test); (D) The expression of Bcl6 and ICOS was evaluated as previous described in CXCR5lowPD-1lowCD4+ T cells and CXCR5highPD-1highCD4+ T cells directly isolated from S. japonicum-infected mice or in vitro induced by macrophages from S. japonicum-infected.
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ppat-1004097-g004: Macrophages drive Tfh cell generation.Expression of CXCR5 versus PD-1 on CD4+ T cells (gated as CD3+CD4+) after co-culture of normal mice derived CD4+ T cells with macrophages (A, B), B cells (E, F), and DCs (G, H) from normal or infected mice in the presence or absence of SEA. Numbers represent the frequency of the boxed population within the CD4+ T cell population; (C) Quantitative RT-PCR analysis of the expression of BCL-6 mRNA in CD4+ T cells cultured with or without macrophage from infected mice. ***, P<0.001; **, P<0.01; *, P<0.05 (Student's t-test); (D) The expression of Bcl6 and ICOS was evaluated as previous described in CXCR5lowPD-1lowCD4+ T cells and CXCR5highPD-1highCD4+ T cells directly isolated from S. japonicum-infected mice or in vitro induced by macrophages from S. japonicum-infected.

Mentions: Macrophages make up approximately 30% of total liver granuloma cells in S. japonicum-infected mice, and most of these macrophages (50–90%) display Ia antigens, acting as professional APCs [36]. Considering macrophages co-locate in spleen and lymph nodes with other two important APCs B cells and DC, and play an important role as APC in induction of the differentiation of Th1 [37], Th2 [38], Th17 [39], [40], and Treg cells [41]–[43], it was interesting to investigate whether macrophages had an effect on the generation of Tfh cells. To address this question, we cultured CD4+ T cells together with macrophages from normal or infected mice in the presence or the absence of soluble egg antigens (SEA) extracted from S. japonicum eggs. SEA is a mixture of antigens including numerous molecules of protein, glycoprotein, glycolipid, lipoprotein and saccharide. SEA provides polyclonal stimulations to immune cells including APC and CD4+ T cells. Results showed that CD4+ T cells not only increased the surface expression of CXCR5 and PD-1 (Figures 4A and 4B) but also upregulated transcripts of the Tfh cell “master regulator” Bcl-6 and ICOS (Figures 4C and 4D) when exposed to macrophages from the infected mice.


Follicular helper T cells promote liver pathology in mice during Schistosoma japonicum infection.

Chen X, Yang X, Li Y, Zhu J, Zhou S, Xu Z, He L, Xue X, Zhang W, Dong X, Wu H, Li CJ, Hsu HT, Kong W, Liu F, Tripathi PB, Yu MS, Chang J, Zhou L, Su C - PLoS Pathog. (2014)

Macrophages drive Tfh cell generation.Expression of CXCR5 versus PD-1 on CD4+ T cells (gated as CD3+CD4+) after co-culture of normal mice derived CD4+ T cells with macrophages (A, B), B cells (E, F), and DCs (G, H) from normal or infected mice in the presence or absence of SEA. Numbers represent the frequency of the boxed population within the CD4+ T cell population; (C) Quantitative RT-PCR analysis of the expression of BCL-6 mRNA in CD4+ T cells cultured with or without macrophage from infected mice. ***, P<0.001; **, P<0.01; *, P<0.05 (Student's t-test); (D) The expression of Bcl6 and ICOS was evaluated as previous described in CXCR5lowPD-1lowCD4+ T cells and CXCR5highPD-1highCD4+ T cells directly isolated from S. japonicum-infected mice or in vitro induced by macrophages from S. japonicum-infected.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4006917&req=5

ppat-1004097-g004: Macrophages drive Tfh cell generation.Expression of CXCR5 versus PD-1 on CD4+ T cells (gated as CD3+CD4+) after co-culture of normal mice derived CD4+ T cells with macrophages (A, B), B cells (E, F), and DCs (G, H) from normal or infected mice in the presence or absence of SEA. Numbers represent the frequency of the boxed population within the CD4+ T cell population; (C) Quantitative RT-PCR analysis of the expression of BCL-6 mRNA in CD4+ T cells cultured with or without macrophage from infected mice. ***, P<0.001; **, P<0.01; *, P<0.05 (Student's t-test); (D) The expression of Bcl6 and ICOS was evaluated as previous described in CXCR5lowPD-1lowCD4+ T cells and CXCR5highPD-1highCD4+ T cells directly isolated from S. japonicum-infected mice or in vitro induced by macrophages from S. japonicum-infected.
Mentions: Macrophages make up approximately 30% of total liver granuloma cells in S. japonicum-infected mice, and most of these macrophages (50–90%) display Ia antigens, acting as professional APCs [36]. Considering macrophages co-locate in spleen and lymph nodes with other two important APCs B cells and DC, and play an important role as APC in induction of the differentiation of Th1 [37], Th2 [38], Th17 [39], [40], and Treg cells [41]–[43], it was interesting to investigate whether macrophages had an effect on the generation of Tfh cells. To address this question, we cultured CD4+ T cells together with macrophages from normal or infected mice in the presence or the absence of soluble egg antigens (SEA) extracted from S. japonicum eggs. SEA is a mixture of antigens including numerous molecules of protein, glycoprotein, glycolipid, lipoprotein and saccharide. SEA provides polyclonal stimulations to immune cells including APC and CD4+ T cells. Results showed that CD4+ T cells not only increased the surface expression of CXCR5 and PD-1 (Figures 4A and 4B) but also upregulated transcripts of the Tfh cell “master regulator” Bcl-6 and ICOS (Figures 4C and 4D) when exposed to macrophages from the infected mice.

Bottom Line: Following Schistosoma japonicum (S. japonicum) infection, granulomatous responses are induced by parasite eggs trapped in host organs, particular in the liver, during the acute stage of disease.While excessive liver granulomatous responses can lead to more severe fibrosis and circulatory impairment in chronically infected host.In addition, our results showed that the generation of Tfh cells driven by macrophages is dependent on cell-cell contact and the level of inducible costimulator ligand (ICOSL) on macrophages which is regulated by CD40-CD40L signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathogen Biology & Immunology, Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, P. R. China.

ABSTRACT
Following Schistosoma japonicum (S. japonicum) infection, granulomatous responses are induced by parasite eggs trapped in host organs, particular in the liver, during the acute stage of disease. While excessive liver granulomatous responses can lead to more severe fibrosis and circulatory impairment in chronically infected host. However, the exact mechanism of hepatic granuloma formation has remained obscure. In this study, we for the first time showed that follicular helper T (Tfh) cells are recruited to the liver to upregulate hepatic granuloma formation and liver injury in S. japonicum-infected mice, and identified a novel function of macrophages in Tfh cell induction. In addition, our results showed that the generation of Tfh cells driven by macrophages is dependent on cell-cell contact and the level of inducible costimulator ligand (ICOSL) on macrophages which is regulated by CD40-CD40L signaling. Our findings uncovered a previously unappreciated role for Tfh cells in liver pathology caused by S. japonicum infection in mice.

Show MeSH
Related in: MedlinePlus