BACKGROUND: IL-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. OBJECTIVE: We 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). METHODS: CD4+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. RESULTS: Intestinal 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. CONCLUSIONS: We 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.
|Titolo:||Intestinal IFN-γ-producing Tr1-cells co-express CCR5 and PD-1, and down-regulate IL-10 in the inflamed gut of IBD patients|
|Parole Chiave:||IBD; IL-10; IL-23; regulatory T-cells|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
|Data di pubblicazione:||2018|
|Data ahead of print / Data di stampa:||21-gen-2018|
|Digital Object Identifier (DOI):||10.1016/j.jaci.2017.12.984|
|Appare nelle tipologie:||01 - Articolo su periodico|