Intestinal IFN-gamma-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

Background: IL-10 is an anti-inflammatory cytokine required for intestinal immune homeostasis. It mediates suppression of T-cell responses by type 1 regulatory T (T(R)1) cells but is also produced by CD25(+) regulatory T (Treg) cells. Objective: We aimed to identify and characterize human intestinal T(R)1 cells and to investigate whether they are a relevant cellular source of IL-10 in patients with inflammatory bowel diseases (IBDs). Methods: 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-1 beta and IL-23 responsiveness was assessed. Results: Intestinal T(R)1 cells could be identified by coexpression of CCR5 and programmed cell death protein 1 (PD-1) in human subjects and mice. CCR5(+) PD-1(+) T(R)1 cells expressed IFN-gamma and efficiently suppressed T-cell proliferation and transfer colitis. Intestinal IFN-gamma(+) T(R)1 cells, but not IL-7 receptor-positive T-H cells or CD25(+) Treg cells, showed lower IL-10 expression in patients with IBDs. T(R)1 cells were responsive to IL-23, and IFN-gamma(+) T(R)1 cells downregulated IL-10 with IL-1 beta and IL-23. Conversely, CD25(+) Treg cells expressed higher levels of IL-1 receptor but showed stable IL-10 expression. Conclusions: We provide the first ex vivo characterization of human intestinal T(R)1 cells. Selective downregulation of IL-10 by IFN-gamma(+) T(R)1 cells in response to proinflammatory cytokines is likely to drive excessive intestinal inflammation in patients with IBDs.