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

• Published in: Nature communications 2018-12, Vol.9 (1), p.5457-14, Article 5457
• Main Authors: Brockmann, Leonie, Soukou, Shiwa, Steglich, Babett, Czarnewski, Paulo, Zhao, Lilan, Wende, Sandra, Bedke, Tanja, Ergen, Can, Manthey, Carolin, Agalioti, Theodora, Geffken, Maria, Seiz, Oliver, Parigi, Sara M., Sorini, Chiara, Geginat, Jens, Fujio, Keishi, Jacobs, Thomas, Roesch, Thomas, Izbicki, Jacob R., Lohse, Ansgar W., Flavell, Richard A., Krebs, Christian, Gustafsson, Jan-Ake, Antonson, Per, Roncarolo, Maria Grazia, Villablanca, Eduardo J., Gagliani, Nicola, Huber, Samuel
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/21; 13/31; 13/95; 14/1; 45/90; 45/91; 631/250/1619/554/1898/1271; 631/250/2502; 631/250/2520; 64/60; 692/4020/1503/257; Animal models; Animals; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; Combinatorial analysis; Gene expression; Heterogeneity; Homeostasis; Humanities and Social Sciences; Humans; Immunoregulation; Inflammatory bowel diseases; Inflammatory Bowel Diseases - immunology; Interleukin 10; Interleukin-10 - metabolism; Intestine; Lymphocytes; Lymphocytes T; Medicin och hälsovetenskap; Mice, Inbred C57BL; multidisciplinary; Receptor mechanisms; Receptors; Science; Science (multidisciplinary); Single-Cell Analysis; Transcription; Transcriptome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07581-4

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 neg 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 neg 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. Tr1 cells are considered an immunosuppressive CD4 T cell population producing IL-10. Here the authors show that IL-10 is insufficient for Tr1 immunosuppression, define surface markers and transcriptional program of the immunosuppressive subset within Tr1, and reveal its deficiency in patients with IBD.