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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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Cholera toxin specific IgA response requires TH17 cellsa) Flow cytometry of PP CD4+ T cells from Tcra−/− mice three months after reconstitution with C57Bl/6 (B6) or Rorc-deficient (Rorc−/−) bone marrow 10 days after cholera toxin challenge, showing expression of CXCR5 and PD-1. b) Proportion of PP CD4+ T cells expressing Foxp3 or producing indicated cytokines in Tcra−/− mice three months after reconstitution with C57Bl/6 or Rorc-deficient bone marrow 10 days after cholera toxin challenge. c, d) ELISA quantification of serum (c) and feces (d) cholera toxin-specific IgA in Tcra−/− and Tcra−/− mice three months after reconstitution with C57Bl/6 or Rorc-deficient bone marrow 10 days after cholera toxin challenge. Mean values +/− SEM for four individual mice are shown. *, p-value ≤ 0.01.
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Figure 7: Cholera toxin specific IgA response requires TH17 cellsa) Flow cytometry of PP CD4+ T cells from Tcra−/− mice three months after reconstitution with C57Bl/6 (B6) or Rorc-deficient (Rorc−/−) bone marrow 10 days after cholera toxin challenge, showing expression of CXCR5 and PD-1. b) Proportion of PP CD4+ T cells expressing Foxp3 or producing indicated cytokines in Tcra−/− mice three months after reconstitution with C57Bl/6 or Rorc-deficient bone marrow 10 days after cholera toxin challenge. c, d) ELISA quantification of serum (c) and feces (d) cholera toxin-specific IgA in Tcra−/− and Tcra−/− mice three months after reconstitution with C57Bl/6 or Rorc-deficient bone marrow 10 days after cholera toxin challenge. Mean values +/− SEM for four individual mice are shown. *, p-value ≤ 0.01.

Mentions: To address if T cell-dependent IgA induction requires TH17 cells in an otherwise intact mouse, we generated bone marrow chimeras in which Tcra−/− hosts were reconstituted with whole bone marrow from Rorc−/− mice21 (Rorc−/−Tcra−/− chimeras), which do not develop TH17 cells22. Although Rorc is required for the development of lymphoid architecture in the mucosal immune system21, 23-24, the mucosal environment of these chimeric mice is not disturbed, as Rorc-expressing innate lymphoid cell types are present in the Tcra−/− hosts. Control Tcra−/− chimeras were reconstituted with bone marrow from wild-type hosts. Flow cytometric analysis of PP showed similar proportions of TFH cells in Rorc−/− and control Tcra−/− chimeras (Fig.7a). Rorc−/−Tcra−/− chimeras had a reduction of IL-17-producing CD4+ T cells compared to control Tcra−/− chimeras, whereas the proportion of Treg was comparable and IFNγ-, IL-4- and IL-13-producing CD4+ T cells were similar or even higher in Rorc−/−Tcra−/− chimeras compared to control Tcra−/− chimeras (Fig.7b). Serum isotype profiles in the two sets of chimeras prior to immunization were similar (Suppl.Fig.2). In order to test for T cell-dependent IgA production, we immunized Rorc−/− and control Tcra−/− chimeras with cholera toxin and analysed serum and fecal IgA amounts 10 days later. Control Tcra−/− chimeras mounted a strong cholera toxin-specific IgA response detectable in serum (Fig.7c) and faeces (Fig.7d). In contrast, Rorc−/−Tcra−/− chimeras had very low levels of cholera toxin-specific IgA, which were comparable to those observed in Tcra−/− mice (Fig.7c,d). Thus, these results show that TH17 cells are required for the germinal center switch to IgA production in PP.


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)

Cholera toxin specific IgA response requires TH17 cellsa) Flow cytometry of PP CD4+ T cells from Tcra−/− mice three months after reconstitution with C57Bl/6 (B6) or Rorc-deficient (Rorc−/−) bone marrow 10 days after cholera toxin challenge, showing expression of CXCR5 and PD-1. b) Proportion of PP CD4+ T cells expressing Foxp3 or producing indicated cytokines in Tcra−/− mice three months after reconstitution with C57Bl/6 or Rorc-deficient bone marrow 10 days after cholera toxin challenge. c, d) ELISA quantification of serum (c) and feces (d) cholera toxin-specific IgA in Tcra−/− and Tcra−/− mice three months after reconstitution with C57Bl/6 or Rorc-deficient bone marrow 10 days after cholera toxin challenge. Mean values +/− SEM for four individual mice are shown. *, p-value ≤ 0.01.
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Related In: Results  -  Collection

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Figure 7: Cholera toxin specific IgA response requires TH17 cellsa) Flow cytometry of PP CD4+ T cells from Tcra−/− mice three months after reconstitution with C57Bl/6 (B6) or Rorc-deficient (Rorc−/−) bone marrow 10 days after cholera toxin challenge, showing expression of CXCR5 and PD-1. b) Proportion of PP CD4+ T cells expressing Foxp3 or producing indicated cytokines in Tcra−/− mice three months after reconstitution with C57Bl/6 or Rorc-deficient bone marrow 10 days after cholera toxin challenge. c, d) ELISA quantification of serum (c) and feces (d) cholera toxin-specific IgA in Tcra−/− and Tcra−/− mice three months after reconstitution with C57Bl/6 or Rorc-deficient bone marrow 10 days after cholera toxin challenge. Mean values +/− SEM for four individual mice are shown. *, p-value ≤ 0.01.
Mentions: To address if T cell-dependent IgA induction requires TH17 cells in an otherwise intact mouse, we generated bone marrow chimeras in which Tcra−/− hosts were reconstituted with whole bone marrow from Rorc−/− mice21 (Rorc−/−Tcra−/− chimeras), which do not develop TH17 cells22. Although Rorc is required for the development of lymphoid architecture in the mucosal immune system21, 23-24, the mucosal environment of these chimeric mice is not disturbed, as Rorc-expressing innate lymphoid cell types are present in the Tcra−/− hosts. Control Tcra−/− chimeras were reconstituted with bone marrow from wild-type hosts. Flow cytometric analysis of PP showed similar proportions of TFH cells in Rorc−/− and control Tcra−/− chimeras (Fig.7a). Rorc−/−Tcra−/− chimeras had a reduction of IL-17-producing CD4+ T cells compared to control Tcra−/− chimeras, whereas the proportion of Treg was comparable and IFNγ-, IL-4- and IL-13-producing CD4+ T cells were similar or even higher in Rorc−/−Tcra−/− chimeras compared to control Tcra−/− chimeras (Fig.7b). Serum isotype profiles in the two sets of chimeras prior to immunization were similar (Suppl.Fig.2). In order to test for T cell-dependent IgA production, we immunized Rorc−/− and control Tcra−/− chimeras with cholera toxin and analysed serum and fecal IgA amounts 10 days later. Control Tcra−/− chimeras mounted a strong cholera toxin-specific IgA response detectable in serum (Fig.7c) and faeces (Fig.7d). In contrast, Rorc−/−Tcra−/− chimeras had very low levels of cholera toxin-specific IgA, which were comparable to those observed in Tcra−/− mice (Fig.7c,d). Thus, these results show that TH17 cells are required for the germinal center switch to IgA production in PP.

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