Intestinal IFN-γ–producing type 1 regulatory T cells coexpress CCR5 and programmed cell death protein 1 and downregulate IL-10 in the inflamed guts of patients with inflammatory bowel disease

IL-10 is an anti-inflammatory cytokine required for intestinal immune homeostasis. It mediates suppression of T-cell responses by type 1 regulatory T (TR1) cells but is also produced by CD25+ regulatory T (Treg) cells. We aimed to identify and characterize human intestinal TR1 cells and to investiga...

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Published in:	Journal of allergy and clinical immunology Vol. 142; no. 5; pp. 1537 - 1547.e8
Main Authors:	Alfen, Johanna Sophie, Larghi, Paola, Facciotti, Federica, Gagliani, Nicola, Bosotti, Roberto, Paroni, Moira, Maglie, Stefano, Gruarin, Paola, Vasco, Chiara Maria, Ranzani, Valeria, Frusteri, Cristina, Iseppon, Andrea, Moro, Monica, Crosti, Maria Cristina, Gatti, Stefano, Pagani, Massimiliano, Caprioli, Flavio, Abrignani, Sergio, Flavell, Richard A., Geginat, Jens
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-11-2018 Elsevier Limited
Subjects:	Apoptosis Biopsy CCR5 protein CD25 antigen CD4 antigen Cell death Cell proliferation Cytokines Disease Flow cytometry Helper cells Homeostasis Human subjects IL-10 IL-1β IL-23 Immunoregulation Inflammatory bowel disease Inflammatory bowel diseases Interleukin 1 Interleukin 1 receptors Interleukin 10 Interleukin 23 Interleukin 7 Intestine Laboratories Lamina propria Lymphocytes Lymphocytes T Mice PD-1 protein Phenotypes regulatory T cells Rodents Ulcerative colitis γ-Interferon Germany CD IL-7R LAG3 PMA Treg IBD FACS IL-23 IL-1R IL-10 UC Inflammatory bowel disease regulatory T cells IL-23R STAT TR1 CRC Foxp3 PD-1 DC
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Summary:	IL-10 is an anti-inflammatory cytokine required for intestinal immune homeostasis. It mediates suppression of T-cell responses by type 1 regulatory T (TR1) cells but is also produced by CD25+ regulatory T (Treg) cells. We aimed to identify and characterize human intestinal TR1 cells and to investigate whether they are a relevant cellular source of IL-10 in patients with inflammatory bowel diseases (IBDs). CD4+ T cells isolated from the intestinal lamina propria of human subjects and mice were analyzed for phenotype, cytokine production, and suppressive capacities. Intracellular IL-10 expression by CD4+ T-cell subsets in the inflamed guts of patients with IBD (Crohn disease or ulcerative colitis) was compared with that in cells from noninflamed control subjects. Finally, the effects of proinflammatory cytokines on T-cell IL-10 expression were analyzed, and IL-1β and IL-23 responsiveness was assessed. Intestinal TR1 cells could be identified by coexpression of CCR5 and programmed cell death protein 1 (PD-1) in human subjects and mice. CCR5+PD-1+ TR1 cells expressed IFN-γ and efficiently suppressed T-cell proliferation and transfer colitis. Intestinal IFN-γ+ TR1 cells, but not IL-7 receptor–positive TH cells or CD25+ Treg cells, showed lower IL-10 expression in patients with IBDs. TR1 cells were responsive to IL-23, and IFN-γ+ TR1 cells downregulated IL-10 with IL-1β and IL-23. Conversely, CD25+ Treg cells expressed higher levels of IL-1 receptor but showed stable IL-10 expression. We provide the first ex vivo characterization of human intestinal TR1 cells. Selective downregulation of IL-10 by IFN-γ+ TR1 cells in response to proinflammatory cytokines is likely to drive excessive intestinal inflammation in patients with IBDs. [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0091-6749 1097-6825
DOI:	10.1016/j.jaci.2017.12.984