Background and aims: Invariant Natural Killer T (iNKT) cells perform pleiotropic functions in different tissues by secreting a vast array of pro-inflammatory and cytotoxic molecules. However, the presence and function of human intestinal iNKT cells capable to secrete immunomodulatory molecules such as IL-10 has never been reported so far. Here we describe for the first time the presence of IL10-producing iNKT cells (NKT10 cells) in the intestinal lamina propria of healthy individuals and of Crohn's Disease (CD) patients. Methods: Frequency and phenotype of NKT10 cells were analyzed ex-vivo from intestinal specimens of Crohn's disease (n=17) and controls (n=7). Stable CD-derived intestinal NKT10 cell lines were used to perform in vitro suppression assays and cocultures with patients'-derived mucosa-associated microbiota. Experimental colitis models were performed by adoptive cell transfer of splenic naïve CD4+ T cells in the presence or absence of IL10-sufficient or deficient iNKT cells. In vivo induction of NKT10 cells was performed by administration of SCFA by oral gavage. Results: Patient's derived intestinal NKT10 cells demonstrated suppressive capabilities towards pathogenic CD4+ T cells. The presence of increased proportions of mucosal NKT10 cells associated with better clinical outcomes in CD patients. Moreover, an intestinal microbial community enriched in SCFA-producing bacteria sustained the production of IL10 by iNKT cells. Finally, IL10- deficient iNKT cell failed to control the pathogenic activity of adoptively transferred CD4+ T cells in an experimental colitis model. Conclusions: These results describe an unprecedent IL10-mediated immunoregulatory role of intestinal iNKT cells in controlling the pathogenic functions of mucosal T-helper subsets and in maintaining the intestinal immune homeostasis.

IL10 secretion endows intestinal human iNKT cells with regulatory functions towards pathogenic T lymphocytes / C. Burrello, F. Strati, G. Lattanzi, A. Diaz-Basabe, E. Mileti, M.R. Giuffrè, G. Lopez, F.M. Cribiù, E. Trombetta, M. Kallikourdis, M. Cremonesi, F. Conforti, F. Botti, L. Porretti, M. Rescigno, M. Vecchi, M.C. Fantini, F. Caprioli, F. Facciotti. - In: JOURNAL OF CROHN'S AND COLITIS. - ISSN 1873-9946. - 16:9(2022 Sep 08), pp. 1461-1474. [10.1093/ecco-jcc/jjac049]

IL10 secretion endows intestinal human iNKT cells with regulatory functions towards pathogenic T lymphocytes

G. Lattanzi;A. Diaz-Basabe;G. Lopez;E. Trombetta;F. Botti;M. Vecchi;F. Caprioli
Penultimo
;
2022

Abstract

Background and aims: Invariant Natural Killer T (iNKT) cells perform pleiotropic functions in different tissues by secreting a vast array of pro-inflammatory and cytotoxic molecules. However, the presence and function of human intestinal iNKT cells capable to secrete immunomodulatory molecules such as IL-10 has never been reported so far. Here we describe for the first time the presence of IL10-producing iNKT cells (NKT10 cells) in the intestinal lamina propria of healthy individuals and of Crohn's Disease (CD) patients. Methods: Frequency and phenotype of NKT10 cells were analyzed ex-vivo from intestinal specimens of Crohn's disease (n=17) and controls (n=7). Stable CD-derived intestinal NKT10 cell lines were used to perform in vitro suppression assays and cocultures with patients'-derived mucosa-associated microbiota. Experimental colitis models were performed by adoptive cell transfer of splenic naïve CD4+ T cells in the presence or absence of IL10-sufficient or deficient iNKT cells. In vivo induction of NKT10 cells was performed by administration of SCFA by oral gavage. Results: Patient's derived intestinal NKT10 cells demonstrated suppressive capabilities towards pathogenic CD4+ T cells. The presence of increased proportions of mucosal NKT10 cells associated with better clinical outcomes in CD patients. Moreover, an intestinal microbial community enriched in SCFA-producing bacteria sustained the production of IL10 by iNKT cells. Finally, IL10- deficient iNKT cell failed to control the pathogenic activity of adoptively transferred CD4+ T cells in an experimental colitis model. Conclusions: These results describe an unprecedent IL10-mediated immunoregulatory role of intestinal iNKT cells in controlling the pathogenic functions of mucosal T-helper subsets and in maintaining the intestinal immune homeostasis.
Crohn’s disease; IL10; iNKT cells; microbiota; SCFA;
Settore MED/04 - Patologia Generale
Settore MED/12 - Gastroenterologia
8-set-2022
31-mar-2022
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/921822
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