Pathogenicity of InVivo generated intestinal Th17 lymphocytes is IFNγ dependent

Giulia Nizzoli, Claudia Burrello, Fulvia Milena Cribiù, Giulia Lovati, Giulia Ercoli, Fiorenzo Botti, Elena Trombetta, Laura Porretti, Katia Todoerti, Antonino Neri, Maria Rita Giuffrè, Jens Geginat, Maurizio Vecchi, Maria Rescigno, Moira Paroni, Flavio Caprioli, Federica Facciotti

Research output: Contribution to journalArticle

2 Citations (Scopus)

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–producingT 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 and Colitis
Volume12
Issue number8
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

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

Keywords

  • Crohn’s disease
  • IFNγ
  • Intestinal permeability
  • Pathogenic determinants
  • Th17

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Pathogenicity of InVivo generated intestinal Th17 lymphocytes is IFNγ dependent. / Nizzoli, Giulia; Burrello, Claudia; Cribiù, Fulvia Milena; Lovati, Giulia; Ercoli, Giulia; Botti, Fiorenzo; Trombetta, Elena; Porretti, Laura; Todoerti, Katia; Neri, Antonino; Giuffrè, Maria Rita; Geginat, Jens; Vecchi, Maurizio; Rescigno, Maria; Paroni, Moira; Caprioli, Flavio; Facciotti, Federica.

In: Journal of Crohn's and Colitis, Vol. 12, No. 8, 01.01.2018, p. 981-992.

Research output: Contribution to journalArticle

Nizzoli, Giulia ; Burrello, Claudia ; Cribiù, Fulvia Milena ; Lovati, Giulia ; Ercoli, Giulia ; Botti, Fiorenzo ; Trombetta, Elena ; Porretti, Laura ; Todoerti, Katia ; Neri, Antonino ; Giuffrè, Maria Rita ; Geginat, Jens ; Vecchi, Maurizio ; Rescigno, Maria ; Paroni, Moira ; Caprioli, Flavio ; Facciotti, Federica. / Pathogenicity of InVivo generated intestinal Th17 lymphocytes is IFNγ dependent. In: Journal of Crohn's and Colitis. 2018 ; Vol. 12, No. 8. pp. 981-992.
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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–producingT 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.",
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T1 - Pathogenicity of InVivo 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 - 2018/1/1

Y1 - 2018/1/1

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–producingT 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–producingT 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 - Crohn’s disease

KW - IFNγ

KW - Intestinal permeability

KW - Pathogenic determinants

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