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J Crohns Colitis. 2018 Jul 30;12(8):981-992. doi: 10.1093/ecco-jcc/jjy051.

Pathogenicity of In Vivo Generated Intestinal Th17 Lymphocytes is IFNγ Dependent.

Author information

1
Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
2
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
3
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
4
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
5
Pathology Unit, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milan, Italy.
6
General and Emergency Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
7
Flow Cytometry Service, Clinical Chemistry and Microbiology Laboratory Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
8
Laboratory of Pre-clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
9
Hematology Unit, Fondazione IRCCS Ca ' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
10
INGM ? National Institute of Molecular Genetics "Romeo ed Enrico Invernizzi" Milan, Italy.
11
Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy.
12
Department of Biosciences, Università degli Studi di Milano, Milan, Italy.

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.

PMID:
29697763
DOI:
10.1093/ecco-jcc/jjy051
[Indexed for MEDLINE]
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