Abstract

Background and Aims: T helper 17 [Th17] cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of interleukin 17A [IL17A], the Th17 signature cytokine, yielded negative results in patients with Crohn's disease [CD], and attempts to elucidate the determinants of Th17 cells' pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells.

Methods: In vivo-generated murine intestinal IL-17-producing T cells were adoptively transferred into immunodeficient Rag1-/- recipients to test their pathogenicity. Human IL-17, IFNγ/IL-17, and IFNγ actively secreting T cell clones were generated from lamina propria lymphocytes of CD patients. The pathogenic activity of intestinal IL-17-producing T cells against the intestinal epithelium was evaluated.

Results: IL-17-producing cells with variable colitogenic activity can be generated in vivo using different experimental colitis models. The pathogenicity of IL-17-secreting cells was directly dependent on their IFNγ secretion capacity, as demonstrated by the reduced colitogenic activity of IL-17-secreting cells isolated from IFNγ-/- mice. Moreover, IFNγ production is a distinguished attribute of CD-derived lamina propria Th17 cells. IFNγ secretion by CD-derived IL-17-producing intestinal clones is directly implicated in the epithelial barrier disruption through the modulation of tight junction proteins.

Conclusions: Intestinal Th17 cell pathogenicity is associated with IFNγ production, which directly affects intestinal permeability through the disruption of epithelial tight junctions.

Original languageEnglish
Pages (from-to)981-992
Number of pages12
JournalJournal of Crohn's & colitis
Volume12
Issue number8
DOIs
Publication statusPublished - Jul 30 2018

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Interleukin-17
Helper-Inducer T-Lymphocytes
Virulence
Th17 Cells
Crohn Disease
T-Lymphocytes
Mucous Membrane
Clone Cells
Tight Junction Proteins
Tight Junctions
Colitis
Intestinal Mucosa
Inflammatory Bowel Diseases
Permeability
Theoretical Models
Pharmacology
Lymphocytes
Cytokines

Keywords

  • Adult
  • Aged
  • Animals
  • Clone Cells/immunology
  • Colitis/immunology
  • Crohn Disease/immunology
  • Female
  • Homeodomain Proteins/genetics
  • Humans
  • Interferon-gamma/genetics
  • Interleukin-17/metabolism
  • Intestinal Mucosa/immunology
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Permeability
  • Th1 Cells/metabolism
  • Th17 Cells/immunology
  • Tight Junctions/metabolism

Cite this

@article{35145f0fe9934a5d891007fb82362cfd,
title = "Pathogenicity of In Vivo Generated Intestinal Th17 Lymphocytes is IFNγ Dependent",
abstract = "Background and Aims: T helper 17 [Th17] cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of interleukin 17A [IL17A], the Th17 signature cytokine, yielded negative results in patients with Crohn's disease [CD], and attempts to elucidate the determinants of Th17 cells' pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells.Methods: In vivo-generated murine intestinal IL-17-producing T cells were adoptively transferred into immunodeficient Rag1-/- recipients to test their pathogenicity. Human IL-17, IFNγ/IL-17, and IFNγ actively secreting T cell clones were generated from lamina propria lymphocytes of CD patients. The pathogenic activity of intestinal IL-17-producing T cells against the intestinal epithelium was evaluated.Results: IL-17-producing cells with variable colitogenic activity can be generated in vivo using different experimental colitis models. The pathogenicity of IL-17-secreting cells was directly dependent on their IFNγ secretion capacity, as demonstrated by the reduced colitogenic activity of IL-17-secreting cells isolated from IFNγ-/- mice. Moreover, IFNγ production is a distinguished attribute of CD-derived lamina propria Th17 cells. IFNγ secretion by CD-derived IL-17-producing intestinal clones is directly implicated in the epithelial barrier disruption through the modulation of tight junction proteins.Conclusions: Intestinal Th17 cell pathogenicity is associated with IFNγ production, which directly affects intestinal permeability through the disruption of epithelial tight junctions.",
keywords = "Adult, Aged, Animals, Clone Cells/immunology, Colitis/immunology, Crohn Disease/immunology, Female, Homeodomain Proteins/genetics, Humans, Interferon-gamma/genetics, Interleukin-17/metabolism, Intestinal Mucosa/immunology, Male, Mice, Mice, Knockout, Middle Aged, Permeability, Th1 Cells/metabolism, Th17 Cells/immunology, Tight Junctions/metabolism",
author = "Giulia Nizzoli and Claudia Burrello and Cribi{\`u}, {Fulvia Milena} and Giulia Lovati and Giulia Ercoli and Fiorenzo Botti and Elena Trombetta and Laura Porretti and Katia Todoerti and Antonino Neri and Giuffr{\`e}, {Maria Rita} and Jens Geginat and Maurizio Vecchi and Maria Rescigno and Moira Paroni and Flavio Caprioli and Federica Facciotti",
year = "2018",
month = "7",
day = "30",
doi = "10.1093/ecco-jcc/jjy051",
language = "English",
volume = "12",
pages = "981--992",
journal = "Journal of Crohn's and Colitis",
issn = "1873-9946",
publisher = "Oxford University Press",
number = "8",

}

TY - JOUR

T1 - Pathogenicity of In Vivo Generated Intestinal Th17 Lymphocytes is IFNγ Dependent

AU - Nizzoli, Giulia

AU - Burrello, Claudia

AU - Cribiù, Fulvia Milena

AU - Lovati, Giulia

AU - Ercoli, Giulia

AU - Botti, Fiorenzo

AU - Trombetta, Elena

AU - Porretti, Laura

AU - Todoerti, Katia

AU - Neri, Antonino

AU - Giuffrè, Maria Rita

AU - Geginat, Jens

AU - Vecchi, Maurizio

AU - Rescigno, Maria

AU - Paroni, Moira

AU - Caprioli, Flavio

AU - Facciotti, Federica

PY - 2018/7/30

Y1 - 2018/7/30

N2 - Background and Aims: T helper 17 [Th17] cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of interleukin 17A [IL17A], the Th17 signature cytokine, yielded negative results in patients with Crohn's disease [CD], and attempts to elucidate the determinants of Th17 cells' pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells.Methods: In vivo-generated murine intestinal IL-17-producing T cells were adoptively transferred into immunodeficient Rag1-/- recipients to test their pathogenicity. Human IL-17, IFNγ/IL-17, and IFNγ actively secreting T cell clones were generated from lamina propria lymphocytes of CD patients. The pathogenic activity of intestinal IL-17-producing T cells against the intestinal epithelium was evaluated.Results: IL-17-producing cells with variable colitogenic activity can be generated in vivo using different experimental colitis models. The pathogenicity of IL-17-secreting cells was directly dependent on their IFNγ secretion capacity, as demonstrated by the reduced colitogenic activity of IL-17-secreting cells isolated from IFNγ-/- mice. Moreover, IFNγ production is a distinguished attribute of CD-derived lamina propria Th17 cells. IFNγ secretion by CD-derived IL-17-producing intestinal clones is directly implicated in the epithelial barrier disruption through the modulation of tight junction proteins.Conclusions: Intestinal Th17 cell pathogenicity is associated with IFNγ production, which directly affects intestinal permeability through the disruption of epithelial tight junctions.

AB - Background and Aims: T helper 17 [Th17] cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of interleukin 17A [IL17A], the Th17 signature cytokine, yielded negative results in patients with Crohn's disease [CD], and attempts to elucidate the determinants of Th17 cells' pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells.Methods: In vivo-generated murine intestinal IL-17-producing T cells were adoptively transferred into immunodeficient Rag1-/- recipients to test their pathogenicity. Human IL-17, IFNγ/IL-17, and IFNγ actively secreting T cell clones were generated from lamina propria lymphocytes of CD patients. The pathogenic activity of intestinal IL-17-producing T cells against the intestinal epithelium was evaluated.Results: IL-17-producing cells with variable colitogenic activity can be generated in vivo using different experimental colitis models. The pathogenicity of IL-17-secreting cells was directly dependent on their IFNγ secretion capacity, as demonstrated by the reduced colitogenic activity of IL-17-secreting cells isolated from IFNγ-/- mice. Moreover, IFNγ production is a distinguished attribute of CD-derived lamina propria Th17 cells. IFNγ secretion by CD-derived IL-17-producing intestinal clones is directly implicated in the epithelial barrier disruption through the modulation of tight junction proteins.Conclusions: Intestinal Th17 cell pathogenicity is associated with IFNγ production, which directly affects intestinal permeability through the disruption of epithelial tight junctions.

KW - Adult

KW - Aged

KW - Animals

KW - Clone Cells/immunology

KW - Colitis/immunology

KW - Crohn Disease/immunology

KW - Female

KW - Homeodomain Proteins/genetics

KW - Humans

KW - Interferon-gamma/genetics

KW - Interleukin-17/metabolism

KW - Intestinal Mucosa/immunology

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Middle Aged

KW - Permeability

KW - Th1 Cells/metabolism

KW - Th17 Cells/immunology

KW - Tight Junctions/metabolism

U2 - 10.1093/ecco-jcc/jjy051

DO - 10.1093/ecco-jcc/jjy051

M3 - Article

C2 - 29697763

VL - 12

SP - 981

EP - 992

JO - Journal of Crohn's and Colitis

JF - Journal of Crohn's and Colitis

SN - 1873-9946

IS - 8

ER -