Intestinal IFN-γ-producing Tr1-cells co-express CCR5 and PD-1, and down-regulate IL-10 in the inflamed gut of IBD patients

Publication date: Available online 31 January 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Johanna Sophie Alfen, Paola Larghi, Federica Facciotti, Nicola Gagliani, Roberto Bosotti, Moira Paroni, Stefano Maglie, Paola Gruarin, Chiara Maria Vasco, Valeria Ranzani, Cristina Frusteri, Andrea Iseppon, Monica Moro, Maria Cristina Crosti, Stefano Gatti, Massimiliano Pagani, Flavio Caprioli, Sergio Abrignani, Richard A. Flavell, Jens Geginat
BackgroundIL-10 is an anti-inflammatory cytokine that is required for intestinal immune homeostasis. It mediates suppression of T-cell responses by type-1 regulatory (Tr1-) cells, but is also produced by CD25⁺ Tregs.ObjectiveWe aimed to identify and characterize human intestinal Tr1-cells, and to investigate if they are a relevant cellular source of IL-10 in inflammatory bowel diseases (IBDs).MethodsCD4⁺T-cells isolated from the intestinal lamina propria of humans and mice were analyzed for phenotype, cytokine production and suppressive capacities. Intracellular IL-10 expression by CD4⁺T-cell subsets in the inflamed gut of IBD patients with Crohn's Disease or Ulcerative Colitis was compared to non-inflamed controls. Finally, the effects of pro-inflammatory cytokines on T-cell IL-10 expression were analyzed, and IL-1P εξπρεσσiον ανδ IL-23 responsiveness were assessed.ResultsIntestinal Tr1-cells could be identified by the co-expression of CCR5 and PD-1 in humans and mice. CCR5⁺PD-1⁺Tr1-cells expressed IFN-γ ανδ ΙL-10 and efficiently suppressed T-cell proliferation and transfer colitis. Intestinal IFN-γ⁺Tr1-cells, but neither IL-7R⁺ helper T-cells nor CD25⁺Tregs, showed lower IL-10 expression in patients with IBDs. Tr1-cells were responsive to IL-23, and IFN-γ⁺Tr1-cells down-regulated IL-10 with IL-1β and IL-23. Conversely, CD25⁺Tregs expressed higher levels of IL-1R, but showed nevertheless stable IL-10 expression.ConclusionsWe provide the first ex vivo characterization of human intestinal Tr1-cells. The selective down-regulation of IL-10 by IFN-γ⁺Tr1-cells in response to pro-inflammatory cytokines is likely to drive excessive intestinal inflammation in IBDs.

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