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Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses.

Hirota K, Turner JE, Villa M, Duarte JH, Demengeot J, Steinmetz OM, Stockinger B - Nat. Immunol. (2013)

Bottom Line: Intestinal Peyer's patches are essential lymphoid organs for the generation of T cell-dependent immunoglobulin A (IgA) for gut homeostasis.Through the use of interleukin 17 (IL-17) fate-reporter mice, we found here that endogenous cells of the TH17 subset of helper T cells in lymphoid organs of naive mice 'preferentially' homed to the intestines and were maintained independently of IL-23.In Peyer's patches, such TH17 cells acquired a follicular helper T cell (TFH cell) phenotype and induced the development of IgA-producing germinal center B cells.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Immunology, Medical Research Council National Institute for Medical Research, Mill Hill, London, UK.

ABSTRACT
Intestinal Peyer's patches are essential lymphoid organs for the generation of T cell-dependent immunoglobulin A (IgA) for gut homeostasis. Through the use of interleukin 17 (IL-17) fate-reporter mice, we found here that endogenous cells of the TH17 subset of helper T cells in lymphoid organs of naive mice 'preferentially' homed to the intestines and were maintained independently of IL-23. In Peyer's patches, such TH17 cells acquired a follicular helper T cell (TFH cell) phenotype and induced the development of IgA-producing germinal center B cells. Mice deficient in TH17 cells failed to generate antigen-specific IgA responses, which provides evidence that TH17 cells are the crucial subset required for the production of high-affinity T cell-dependent IgA.

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Induction of B cell IgA by TH17 cellsa) Quantitative PCR analysis for expression of Aicda in FACS purified B220+ cells from LN or PP of C57Bl/6 (B6), Tcra−/− or Tcra−/− mice transferred with eYFP+ TH17 cells (TH17 Tcra−/−). b) Flow cytometry of B220+ cells (left panel) and B220+ GL-7+ CD95+ cells (right panel) from PP of B6, Tcra−/− or Tcra−/− mice transferred with eYFP+ TH17 cells showing expression of germinal center markers CD95 and GL-7 (left) and IgA (right). c) Proportion of B220+ GL-7+ CD95+ and B220+ GL-7+ CD95+ IgA+ cells from B6, Tcra−/− and Tcra−/− mice transferred with eYFP+ TH17 cells. Mean values +/− SD for three individual mice are shown. Data in a, b and c are representative of three independent experiments. d) ELISA quantification of serum immunoglobulin isotypes from B6, Tcra−/− and Tcra−/− mice transferred with CD4+ CD44high eYFP− (CD44highTcra−/−) or with eYFP+ TH17 cells (TH17 Tcra−/−). *, p-value < 0.01.
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Figure 4: Induction of B cell IgA by TH17 cellsa) Quantitative PCR analysis for expression of Aicda in FACS purified B220+ cells from LN or PP of C57Bl/6 (B6), Tcra−/− or Tcra−/− mice transferred with eYFP+ TH17 cells (TH17 Tcra−/−). b) Flow cytometry of B220+ cells (left panel) and B220+ GL-7+ CD95+ cells (right panel) from PP of B6, Tcra−/− or Tcra−/− mice transferred with eYFP+ TH17 cells showing expression of germinal center markers CD95 and GL-7 (left) and IgA (right). c) Proportion of B220+ GL-7+ CD95+ and B220+ GL-7+ CD95+ IgA+ cells from B6, Tcra−/− and Tcra−/− mice transferred with eYFP+ TH17 cells. Mean values +/− SD for three individual mice are shown. Data in a, b and c are representative of three independent experiments. d) ELISA quantification of serum immunoglobulin isotypes from B6, Tcra−/− and Tcra−/− mice transferred with CD4+ CD44high eYFP− (CD44highTcra−/−) or with eYFP+ TH17 cells (TH17 Tcra−/−). *, p-value < 0.01.

Mentions: The dependency of intestinal TH17 cells on commensal bacteria raises the possibility that TFH cells developing from gut homing ex-TH17 cells may be specialized for helping B cell IgA responses in PP germinal centers. We therefore analysed B cell expression of Aicda, which is required for somatic hypermutation, gene conversion and class-switch recombination of immunoglobulin genes. There was little Aicda expression in LN B cells of B6 mice, in line with the absence of germinal centers in mice that are kept under specific pathogen free (SPF) conditions. B cells in PP on the other hand are continuously stimulated by the commensal flora and expressed high levels of Aicda (Fig.4a). In absence of T cells in Tcra-deficient hosts, Aicda expression was very low (Fig.4a), as no germinal center B cells develop in the absence of T cell help. Transfer of eYFP+ TH17 cells, however, reconstituted Aicda expression to the level seen in B6 mice (Fig.4a).


Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses.

Hirota K, Turner JE, Villa M, Duarte JH, Demengeot J, Steinmetz OM, Stockinger B - Nat. Immunol. (2013)

Induction of B cell IgA by TH17 cellsa) Quantitative PCR analysis for expression of Aicda in FACS purified B220+ cells from LN or PP of C57Bl/6 (B6), Tcra−/− or Tcra−/− mice transferred with eYFP+ TH17 cells (TH17 Tcra−/−). b) Flow cytometry of B220+ cells (left panel) and B220+ GL-7+ CD95+ cells (right panel) from PP of B6, Tcra−/− or Tcra−/− mice transferred with eYFP+ TH17 cells showing expression of germinal center markers CD95 and GL-7 (left) and IgA (right). c) Proportion of B220+ GL-7+ CD95+ and B220+ GL-7+ CD95+ IgA+ cells from B6, Tcra−/− and Tcra−/− mice transferred with eYFP+ TH17 cells. Mean values +/− SD for three individual mice are shown. Data in a, b and c are representative of three independent experiments. d) ELISA quantification of serum immunoglobulin isotypes from B6, Tcra−/− and Tcra−/− mice transferred with CD4+ CD44high eYFP− (CD44highTcra−/−) or with eYFP+ TH17 cells (TH17 Tcra−/−). *, p-value < 0.01.
© Copyright Policy
Related In: Results  -  Collection

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Figure 4: Induction of B cell IgA by TH17 cellsa) Quantitative PCR analysis for expression of Aicda in FACS purified B220+ cells from LN or PP of C57Bl/6 (B6), Tcra−/− or Tcra−/− mice transferred with eYFP+ TH17 cells (TH17 Tcra−/−). b) Flow cytometry of B220+ cells (left panel) and B220+ GL-7+ CD95+ cells (right panel) from PP of B6, Tcra−/− or Tcra−/− mice transferred with eYFP+ TH17 cells showing expression of germinal center markers CD95 and GL-7 (left) and IgA (right). c) Proportion of B220+ GL-7+ CD95+ and B220+ GL-7+ CD95+ IgA+ cells from B6, Tcra−/− and Tcra−/− mice transferred with eYFP+ TH17 cells. Mean values +/− SD for three individual mice are shown. Data in a, b and c are representative of three independent experiments. d) ELISA quantification of serum immunoglobulin isotypes from B6, Tcra−/− and Tcra−/− mice transferred with CD4+ CD44high eYFP− (CD44highTcra−/−) or with eYFP+ TH17 cells (TH17 Tcra−/−). *, p-value < 0.01.
Mentions: The dependency of intestinal TH17 cells on commensal bacteria raises the possibility that TFH cells developing from gut homing ex-TH17 cells may be specialized for helping B cell IgA responses in PP germinal centers. We therefore analysed B cell expression of Aicda, which is required for somatic hypermutation, gene conversion and class-switch recombination of immunoglobulin genes. There was little Aicda expression in LN B cells of B6 mice, in line with the absence of germinal centers in mice that are kept under specific pathogen free (SPF) conditions. B cells in PP on the other hand are continuously stimulated by the commensal flora and expressed high levels of Aicda (Fig.4a). In absence of T cells in Tcra-deficient hosts, Aicda expression was very low (Fig.4a), as no germinal center B cells develop in the absence of T cell help. Transfer of eYFP+ TH17 cells, however, reconstituted Aicda expression to the level seen in B6 mice (Fig.4a).

Bottom Line: Intestinal Peyer's patches are essential lymphoid organs for the generation of T cell-dependent immunoglobulin A (IgA) for gut homeostasis.Through the use of interleukin 17 (IL-17) fate-reporter mice, we found here that endogenous cells of the TH17 subset of helper T cells in lymphoid organs of naive mice 'preferentially' homed to the intestines and were maintained independently of IL-23.In Peyer's patches, such TH17 cells acquired a follicular helper T cell (TFH cell) phenotype and induced the development of IgA-producing germinal center B cells.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Immunology, Medical Research Council National Institute for Medical Research, Mill Hill, London, UK.

ABSTRACT
Intestinal Peyer's patches are essential lymphoid organs for the generation of T cell-dependent immunoglobulin A (IgA) for gut homeostasis. Through the use of interleukin 17 (IL-17) fate-reporter mice, we found here that endogenous cells of the TH17 subset of helper T cells in lymphoid organs of naive mice 'preferentially' homed to the intestines and were maintained independently of IL-23. In Peyer's patches, such TH17 cells acquired a follicular helper T cell (TFH cell) phenotype and induced the development of IgA-producing germinal center B cells. Mice deficient in TH17 cells failed to generate antigen-specific IgA responses, which provides evidence that TH17 cells are the crucial subset required for the production of high-affinity T cell-dependent IgA.

Show MeSH
Related in: MedlinePlus