Molecular and functional heterogeneity of IL-10-producing CD4 T cells.
Leonie Brockmann, Shiwa Soukou, Babett Steglich, Paulo Czarnewski, Lilan Zhao, Sandra Wende, Tanja Bedke, Can Ergen, Carolin Manthey, Theodora Agalioti, Maria Geffken, Oliver Seiz, Sara M Parigi, Chiara Sorini, Jens Geginat, Keishi Fujio, Thomas Jacobs, Thomas Roesch, Jacob R Izbicki, Ansgar W Lohse, Richard A Flavell, Christian Krebs, Jan-Ake Gustafsson, Per Antonson, Maria Grazia Roncarolo, Eduardo J Villablanca, Nicola Gagliani, Samuel Huber
Author Information
Leonie Brockmann: I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Shiwa Soukou: I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Babett Steglich: I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Paulo Czarnewski: Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, 17176, Stockholm, Sweden. ORCID
Lilan Zhao: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Sandra Wende: I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Tanja Bedke: I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Can Ergen: I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Carolin Manthey: I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Theodora Agalioti: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Maria Geffken: Institute of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Oliver Seiz: I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Sara M Parigi: Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, 17176, Stockholm, Sweden.
Chiara Sorini: Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, 17176, Stockholm, Sweden. ORCID
Jens Geginat: INGM-National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", 20122, Milan, Italy.
Keishi Fujio: Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 113-8655, Tokyo, Japan.
Thomas Jacobs: Department of Immunology, Bernhard-Nocht-Institute of Tropical Medicine, 20359, Hamburg, Germany.
Thomas Roesch: Department for Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Jacob R Izbicki: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Ansgar W Lohse: I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Richard A Flavell: Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, 06520, USA. ORCID
Christian Krebs: III. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Jan-Ake Gustafsson: Department of Biosciences and Nutrition, Karolinska Institutet, 17177, Stockholm, Sweden.
Per Antonson: Department of Biosciences and Nutrition, Karolinska Institutet, 17177, Stockholm, Sweden.
Maria Grazia Roncarolo: Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, ISCBRM, Stanford School of Medicine, 94304, Stanford, CA, USA.
Eduardo J Villablanca: Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, 17176, Stockholm, Sweden. ORCID
Nicola Gagliani: I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. n.gagliani@uke.de.
Samuel Huber: I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. shuber@uke.de.
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 Foxp3 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 Foxp3 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.
