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J Allergy Clin Immunol. 2018 Nov;142(5):1537-1547.e8. doi: 10.1016/j.jaci.2017.12.984. Epub 2018 Jan 31.

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.

Author information

1
INGM-National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi" Milan, Milan, Italy.
2
INGM-National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi" Milan, Milan, Italy; Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy.
3
Department of Medicine & Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Immunobiology, School of Medicine, Yale University, New Haven, Conn.
4
Unità Operativa di Gastroenterologia ed Endoscopia, Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
5
Department of Immunobiology, School of Medicine, Yale University, New Haven, Conn.
6
Centro Ricerche Precliniche, Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
7
INGM-National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi" Milan, Milan, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
8
Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy; Unità Operativa di Gastroenterologia ed Endoscopia, Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
9
INGM-National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi" Milan, Milan, Italy; Department of Clinical Science and Community Health (DISCCO), University of Milan, Milan, Italy.
10
Department of Immunobiology, School of Medicine, Yale University, New Haven, Conn; Howard Hughes Medical Institute, School of Medicine, Yale University, New Haven, Conn.
11
INGM-National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi" Milan, Milan, Italy. Electronic address: geginat@ingm.org.

Abstract

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 (TR1) cells but is also produced by CD25+ regulatory T (Treg) cells.

OBJECTIVE:

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).

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-1β and IL-23 responsiveness was assessed.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

IL-10; IL-23; Inflammatory bowel disease; regulatory T cells

PMID:
29369775
DOI:
10.1016/j.jaci.2017.12.984
[Indexed for MEDLINE]
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