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Nat Commun. 2018 Dec 21;9(1):5457. doi: 10.1038/s41467-018-07581-4.

Molecular and functional heterogeneity of IL-10-producing CD4+ T cells.

Author information

1
I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
2
Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
3
Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, 17176, Stockholm, Sweden.
4
Institute of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
5
INGM-National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", 20122, Milan, Italy.
6
Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 113-8655, Tokyo, Japan.
7
Department of Immunology, Bernhard-Nocht-Institute of Tropical Medicine, 20359, Hamburg, Germany.
8
Department for Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
9
Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, 06520, USA.
10
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, 06520, USA.
11
III. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
12
Department of Biosciences and Nutrition, Karolinska Institutet, 17177, Stockholm, Sweden.
13
Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, ISCBRM, Stanford School of Medicine, 94304, Stanford, CA, USA.
14
I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. n.gagliani@uke.de.
15
Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. n.gagliani@uke.de.
16
Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, 17176, Stockholm, Sweden. n.gagliani@uke.de.
17
I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. shuber@uke.de.

Abstract

IL-10 is a prototypical anti-inflammatory cytokine, which is fundamental to the maintenance of immune homeostasis, especially in the intestine. There is an assumption that cells producing IL-10 have an immunoregulatory function. However, here we report that IL-10-producing CD4+ T cells are phenotypically and functionally heterogeneous. By combining single cell transcriptome and functional analyses, we identified a subpopulation of IL-10-producing Foxp3neg CD4+ T cells that displays regulatory activity unlike other IL-10-producing CD4+ T cells, which are unexpectedly pro-inflammatory. The combinatorial expression of co-inhibitory receptors is sufficient to discriminate IL-10-producing CD4+ T cells with regulatory function from others and to identify them across different tissues and disease models in mice and humans. These regulatory IL-10-producing Foxp3neg CD4+ T cells have a unique transcriptional program, which goes beyond the regulation of IL-10 expression. Finally, we found that patients with Inflammatory Bowel Disease demonstrate a deficiency in this specific regulatory T-cell subpopulation.

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