Pathogenicity of In Vivo Generated Intestinal Th17 Lymphocytes is IFNγ Dependent

Autor:	Giulia Lovati, Maria Rescigno, Fulvia Milena Cribiù, Jens Geginat, Antonino Neri, Giulia Nizzoli, Katia Todoerti, Laura Porretti, Elena Trombetta, Claudia Burrello, Flavio Caprioli, Maurizio Vecchi, Fiorenzo Botti, Maria Rita Giuffrè, Federica Facciotti, Giulia Ercoli, Moira Paroni
Přispěvatelé:	Nizzoli, G, Burrello, C, Cribiu, F, Lovati, G, Ercoli, G, Botti, F, Trombetta, E, Porretti, L, Todoerti, K, Neri, A, Giuffre, M, Geginat, J, Vecchi, M, Rescigno, M, Paroni, M, Caprioli, F, Facciotti, F
Rok vydání:	2018
Předmět:	Adult Male Crohn’s disease 0301 basic medicine medicine.medical_treatment T cell Permeability Tight Junctions Interferon-gamma Mice 03 medical and health sciences 0302 clinical medicine Crohn Disease medicine Animals Humans Secretion Intestinal Mucosa Aged Homeodomain Proteins Mice Knockout Lamina propria Intestinal permeability Tight junction intestinal permeability business.industry Interleukin-17 Gastroenterology General Medicine Middle Aged Th1 Cells Colitis medicine.disease Intestinal epithelium Clone Cells 030104 developmental biology Cytokine medicine.anatomical_structure 030220 oncology & carcinogenesis Immunology pathogenic determinant Th17 Cells Female Th17 Interleukin 17 business IFNγ
Zdroj:	Journal of Crohn's and Colitis. 12:981-992
ISSN:	1876-4479 1873-9946
DOI:	10.1093/ecco-jcc/jjy051
Popis:	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, IFN gamma/IL-17, and IFN gamma 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 IFN gamma secretion capacity, as demonstrated by the reduced colitogenic activity of IL-17-secreting cells isolated from IFN gamma(-/-) mice. Moreover, IFN gamma production is a distinguished attribute of CD-derived lamina propria Th17 cells. IFN gamma 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 IFN gamma production, which directly affects intestinal permeability through the disruption of epithelial tight junctions.
Databáze:	OpenAIRE
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