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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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Co-transfer of eYFP+ TH17 with CD25high (Foxp3+) Treg cellsa) Flow cytometry of FACS sorted CD45.1+ CD4+ CD25high T cells showing Foxp3 staining b) Flow cytometry of transferred CD45.1+ and eYFP+ cells in LN, PP, and LP of Tcra−/− mice three months after transfer. c) Flow cytometry of transferred CD45.1+ (left panel) and eYFP+ (right panel) cells in LN, PP, and LP of Tcra−/− mice three months after transfer showing Foxp3 staining. d) Flow cytometry of transferred CD45.1 (left panel) and eYFP+ (right panel) cells in LN, PP, and LP three months after transfer showing CXCR5 and PD-1 expression. Data in a, b, c and d are representative of three independent experiments. e) Proportion of CXCR5+ PD-1high cells and f) proportion of B220+ GL-7+ CD95+ (GC) B cells in PP of Tcra−/− mice three months after transfer with eYFP+ TH17 (PP TH17 Tcra−/−) or CD45.1+ CD4+ RFPhigh T cells (PP TregTcra−/−). Mean values +/− SD for three individual mice are shown. g) Serum IgA levels from Tcra−/−, PP TH17 Tcra−/− and PP TregTcra−/− mice 3 months after transfer.
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Figure 5: Co-transfer of eYFP+ TH17 with CD25high (Foxp3+) Treg cellsa) Flow cytometry of FACS sorted CD45.1+ CD4+ CD25high T cells showing Foxp3 staining b) Flow cytometry of transferred CD45.1+ and eYFP+ cells in LN, PP, and LP of Tcra−/− mice three months after transfer. c) Flow cytometry of transferred CD45.1+ (left panel) and eYFP+ (right panel) cells in LN, PP, and LP of Tcra−/− mice three months after transfer showing Foxp3 staining. d) Flow cytometry of transferred CD45.1 (left panel) and eYFP+ (right panel) cells in LN, PP, and LP three months after transfer showing CXCR5 and PD-1 expression. Data in a, b, c and d are representative of three independent experiments. e) Proportion of CXCR5+ PD-1high cells and f) proportion of B220+ GL-7+ CD95+ (GC) B cells in PP of Tcra−/− mice three months after transfer with eYFP+ TH17 (PP TH17 Tcra−/−) or CD45.1+ CD4+ RFPhigh T cells (PP TregTcra−/−). Mean values +/− SD for three individual mice are shown. g) Serum IgA levels from Tcra−/−, PP TH17 Tcra−/− and PP TregTcra−/− mice 3 months after transfer.

Mentions: Previous reports suggested that Foxp3+ regulatory T (Treg) cells might adopt a TFH phenotype in PP8, 18-20. Since these studies had focused on Treg isolated from lymphoid organs, we first compared the homing as well as the adoption of a TFH phenotype in Treg and TH17 cells isolated from LN and spleen. Treg from B6.CD45.1 mice were isolated on the basis of high CD25 expression, which correlated well with Foxp3 expression (Fig.5a), and co-transferred with equal numbers of eYFP+ TH17 cells into Tcra-deficient hosts. Three months later, transferred Treg were preferentially found in LN, whereas transferred eYFP+ cells homed to LP and PP of the small intestine (Fig.5b). CD45.1+ donor Treg retained their Foxp3 expression and there was no indication that donor eYFP+ TH17 cells acquired Foxp3 expression in any location within the adoptive host (Fig.5c). Furthermore, while 15-30% of TH17 cells deviated to a TFH profile in PP, Treg cells did not acquire a TFH profile in any of the tissues examined (Fig.5d). As the poor homing of LN derived Treg to intestinal tissues might have precluded acquisition of a TFH phenotype in PP, we isolated RFPhigh Treg from LP and PP of Foxp3RFP and transferred them into Tcra-deficient hosts. Although we observed efficient homing of donor RFPhigh Treg into PP, these cells did not acquire a TFH profile in the adoptive hosts (Fig.5e). Furthermore, adoptive Treg transfer did not induce germinal center B cells and IgA production (Fig.5f,g). Taken together these data strongly suggest that the promotion of IgA class switching in GC B cells in the PP is a function of ex-TH17 derived TFH cells, whereas Treg neither adopt a TFH profile nor support IgA production.


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)

Co-transfer of eYFP+ TH17 with CD25high (Foxp3+) Treg cellsa) Flow cytometry of FACS sorted CD45.1+ CD4+ CD25high T cells showing Foxp3 staining b) Flow cytometry of transferred CD45.1+ and eYFP+ cells in LN, PP, and LP of Tcra−/− mice three months after transfer. c) Flow cytometry of transferred CD45.1+ (left panel) and eYFP+ (right panel) cells in LN, PP, and LP of Tcra−/− mice three months after transfer showing Foxp3 staining. d) Flow cytometry of transferred CD45.1 (left panel) and eYFP+ (right panel) cells in LN, PP, and LP three months after transfer showing CXCR5 and PD-1 expression. Data in a, b, c and d are representative of three independent experiments. e) Proportion of CXCR5+ PD-1high cells and f) proportion of B220+ GL-7+ CD95+ (GC) B cells in PP of Tcra−/− mice three months after transfer with eYFP+ TH17 (PP TH17 Tcra−/−) or CD45.1+ CD4+ RFPhigh T cells (PP TregTcra−/−). Mean values +/− SD for three individual mice are shown. g) Serum IgA levels from Tcra−/−, PP TH17 Tcra−/− and PP TregTcra−/− mice 3 months after transfer.
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Figure 5: Co-transfer of eYFP+ TH17 with CD25high (Foxp3+) Treg cellsa) Flow cytometry of FACS sorted CD45.1+ CD4+ CD25high T cells showing Foxp3 staining b) Flow cytometry of transferred CD45.1+ and eYFP+ cells in LN, PP, and LP of Tcra−/− mice three months after transfer. c) Flow cytometry of transferred CD45.1+ (left panel) and eYFP+ (right panel) cells in LN, PP, and LP of Tcra−/− mice three months after transfer showing Foxp3 staining. d) Flow cytometry of transferred CD45.1 (left panel) and eYFP+ (right panel) cells in LN, PP, and LP three months after transfer showing CXCR5 and PD-1 expression. Data in a, b, c and d are representative of three independent experiments. e) Proportion of CXCR5+ PD-1high cells and f) proportion of B220+ GL-7+ CD95+ (GC) B cells in PP of Tcra−/− mice three months after transfer with eYFP+ TH17 (PP TH17 Tcra−/−) or CD45.1+ CD4+ RFPhigh T cells (PP TregTcra−/−). Mean values +/− SD for three individual mice are shown. g) Serum IgA levels from Tcra−/−, PP TH17 Tcra−/− and PP TregTcra−/− mice 3 months after transfer.
Mentions: Previous reports suggested that Foxp3+ regulatory T (Treg) cells might adopt a TFH phenotype in PP8, 18-20. Since these studies had focused on Treg isolated from lymphoid organs, we first compared the homing as well as the adoption of a TFH phenotype in Treg and TH17 cells isolated from LN and spleen. Treg from B6.CD45.1 mice were isolated on the basis of high CD25 expression, which correlated well with Foxp3 expression (Fig.5a), and co-transferred with equal numbers of eYFP+ TH17 cells into Tcra-deficient hosts. Three months later, transferred Treg were preferentially found in LN, whereas transferred eYFP+ cells homed to LP and PP of the small intestine (Fig.5b). CD45.1+ donor Treg retained their Foxp3 expression and there was no indication that donor eYFP+ TH17 cells acquired Foxp3 expression in any location within the adoptive host (Fig.5c). Furthermore, while 15-30% of TH17 cells deviated to a TFH profile in PP, Treg cells did not acquire a TFH profile in any of the tissues examined (Fig.5d). As the poor homing of LN derived Treg to intestinal tissues might have precluded acquisition of a TFH phenotype in PP, we isolated RFPhigh Treg from LP and PP of Foxp3RFP and transferred them into Tcra-deficient hosts. Although we observed efficient homing of donor RFPhigh Treg into PP, these cells did not acquire a TFH profile in the adoptive hosts (Fig.5e). Furthermore, adoptive Treg transfer did not induce germinal center B cells and IgA production (Fig.5f,g). Taken together these data strongly suggest that the promotion of IgA class switching in GC B cells in the PP is a function of ex-TH17 derived TFH cells, whereas Treg neither adopt a TFH profile nor support IgA production.

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