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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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Preferential migration of eYFP+ TH17 cells into gut-associated tissuesa) Flow cytometry of CD4+ eYFP+ T cells (solid line) and CD4+ CD44high eYFP− T cells (shaded line) isolated from LN and spleen of Il17aCreR26ReYFP mice. The percentage of cells expressing the indicated marker is shown in the histogram. Isotype controls were used as negative controls indicated by placement of the bars. (b) Proportion of eYFP+ TH17 cells in LN, PP and LP of SPF and germfree (GF) Il17aCreR26ReYFP mice. (c,d) Flow cytometry of CD4+ T cells in LN, PP and LP cells of Tcra−/− mice reconstituted with CD4+ eYFP+ TH17 cells and CD45.1+ eYFP− CD44high CD4+ T cells, as assessed three months after transfer. Mean values +/− SD for three individual mice are shown. Data are representative of three independent experiments.
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Figure 1: Preferential migration of eYFP+ TH17 cells into gut-associated tissuesa) Flow cytometry of CD4+ eYFP+ T cells (solid line) and CD4+ CD44high eYFP− T cells (shaded line) isolated from LN and spleen of Il17aCreR26ReYFP mice. The percentage of cells expressing the indicated marker is shown in the histogram. Isotype controls were used as negative controls indicated by placement of the bars. (b) Proportion of eYFP+ TH17 cells in LN, PP and LP of SPF and germfree (GF) Il17aCreR26ReYFP mice. (c,d) Flow cytometry of CD4+ T cells in LN, PP and LP cells of Tcra−/− mice reconstituted with CD4+ eYFP+ TH17 cells and CD45.1+ eYFP− CD44high CD4+ T cells, as assessed three months after transfer. Mean values +/− SD for three individual mice are shown. Data are representative of three independent experiments.

Mentions: TH17 cells constitute approximately 0.1 % of CD4+ T helper cells in the peripheral lymph nodes (LN) and spleen in non-immune IL-17 fate reporter mice (Il17aCreR26ReYFP mice) in which IL-17-producing cells are permanently marked as eYFP+ cells12. This system is a powerful tool to track TH17 cells and investigate potential plasticity towards alternative effector functions, as detection of these cells does not depend on staining for intracellular IL-17. Flow cytometric analysis of eYFP+ TH17 cells from LN of Il17aCreR26ReYFP mice showed almost uniform surface expression of CCR6, IL-7Rα, CD25, CD103 and ICOS as well as expression of the signature cytokine IL-17 and the transcription factor RORγt (Fig.1a). Expression of CCR6 and CD103 suggested gut homing capacity, because the CCR6 ligand CCL20 is known to be expressed in the small intestine13. As intestinal TH17 cells are dependent on the gut microbiota and absent in germfree mice4, we compared the proportions of eYFP+ TH17 cells in LN, PP and LP of SPF or germfree Il17aCreR26ReYFP mice. eYFP+ TH17 cells were undetectable in PP and LP and also almost completely absent from LN of germfree Il17aCreR26ReYFP mice (Fig.1b). To test the homing properties of TH17 cells compared with other memory type T cells from non-immune mice, we sorted eYFP+ TH17 cells and eYFP− CD4+ T cells with an activated phenotype (CD44high) from LN of Il17aCreR26ReYFP mice (distinguished by expression of the allotypic marker CD45.1) and adoptively co-transferred them in a 1:1 ratio into Tcra-deficient hosts (CD45.2), which lack conventional CD4+ and CD8+ T cells. eYFP+ TH17 cells preferentially reconstituted the gut-associated tissues, such as the LP and PP of the small intestine, but not the peripheral lymph nodes where the cells had originally resided (Fig.1c,d). In contrast, eYFP− CD44high CD45.1+ non-TH17 cells preferentially seeded peripheral LN (Fig.1c,d). Thus, the majority of TH17 cells found in lymphoid organs of non-immune mice have gut-homing properties.


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)

Preferential migration of eYFP+ TH17 cells into gut-associated tissuesa) Flow cytometry of CD4+ eYFP+ T cells (solid line) and CD4+ CD44high eYFP− T cells (shaded line) isolated from LN and spleen of Il17aCreR26ReYFP mice. The percentage of cells expressing the indicated marker is shown in the histogram. Isotype controls were used as negative controls indicated by placement of the bars. (b) Proportion of eYFP+ TH17 cells in LN, PP and LP of SPF and germfree (GF) Il17aCreR26ReYFP mice. (c,d) Flow cytometry of CD4+ T cells in LN, PP and LP cells of Tcra−/− mice reconstituted with CD4+ eYFP+ TH17 cells and CD45.1+ eYFP− CD44high CD4+ T cells, as assessed three months after transfer. Mean values +/− SD for three individual mice are shown. Data are representative of three independent experiments.
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Related In: Results  -  Collection

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Figure 1: Preferential migration of eYFP+ TH17 cells into gut-associated tissuesa) Flow cytometry of CD4+ eYFP+ T cells (solid line) and CD4+ CD44high eYFP− T cells (shaded line) isolated from LN and spleen of Il17aCreR26ReYFP mice. The percentage of cells expressing the indicated marker is shown in the histogram. Isotype controls were used as negative controls indicated by placement of the bars. (b) Proportion of eYFP+ TH17 cells in LN, PP and LP of SPF and germfree (GF) Il17aCreR26ReYFP mice. (c,d) Flow cytometry of CD4+ T cells in LN, PP and LP cells of Tcra−/− mice reconstituted with CD4+ eYFP+ TH17 cells and CD45.1+ eYFP− CD44high CD4+ T cells, as assessed three months after transfer. Mean values +/− SD for three individual mice are shown. Data are representative of three independent experiments.
Mentions: TH17 cells constitute approximately 0.1 % of CD4+ T helper cells in the peripheral lymph nodes (LN) and spleen in non-immune IL-17 fate reporter mice (Il17aCreR26ReYFP mice) in which IL-17-producing cells are permanently marked as eYFP+ cells12. This system is a powerful tool to track TH17 cells and investigate potential plasticity towards alternative effector functions, as detection of these cells does not depend on staining for intracellular IL-17. Flow cytometric analysis of eYFP+ TH17 cells from LN of Il17aCreR26ReYFP mice showed almost uniform surface expression of CCR6, IL-7Rα, CD25, CD103 and ICOS as well as expression of the signature cytokine IL-17 and the transcription factor RORγt (Fig.1a). Expression of CCR6 and CD103 suggested gut homing capacity, because the CCR6 ligand CCL20 is known to be expressed in the small intestine13. As intestinal TH17 cells are dependent on the gut microbiota and absent in germfree mice4, we compared the proportions of eYFP+ TH17 cells in LN, PP and LP of SPF or germfree Il17aCreR26ReYFP mice. eYFP+ TH17 cells were undetectable in PP and LP and also almost completely absent from LN of germfree Il17aCreR26ReYFP mice (Fig.1b). To test the homing properties of TH17 cells compared with other memory type T cells from non-immune mice, we sorted eYFP+ TH17 cells and eYFP− CD4+ T cells with an activated phenotype (CD44high) from LN of Il17aCreR26ReYFP mice (distinguished by expression of the allotypic marker CD45.1) and adoptively co-transferred them in a 1:1 ratio into Tcra-deficient hosts (CD45.2), which lack conventional CD4+ and CD8+ T cells. eYFP+ TH17 cells preferentially reconstituted the gut-associated tissues, such as the LP and PP of the small intestine, but not the peripheral lymph nodes where the cells had originally resided (Fig.1c,d). In contrast, eYFP− CD44high CD45.1+ non-TH17 cells preferentially seeded peripheral LN (Fig.1c,d). Thus, the majority of TH17 cells found in lymphoid organs of non-immune mice have gut-homing properties.

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