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

doi:10.1038/s41467-018-07581-4

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. LohseRichard A. Flavell, Christian Krebs, Jan Ake Gustafsson, Per Antonson, Maria Grazia Roncarolo, Eduardo J. Villablanca, Nicola Gagliani, Samuel Huber

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

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 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.

Original language	English (US)
Article number	5457
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07581-4
State	Published - Dec 1 2018

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-018-07581-4

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Brockmann, L., Soukou, S., Steglich, B., Czarnewski, P., Zhao, L., Wende, S., Bedke, T., Ergen, C., Manthey, C., Agalioti, T., Geffken, M., Seiz, O., Parigi, S. M., Sorini, C., Geginat, J., Fujio, K., Jacobs, T., Roesch, T., Izbicki, J. R., ... Huber, S. (2018). Molecular and functional heterogeneity of IL-10-producing CD4 ⁺ T cells Nature Communications, 9(1), [5457]. https://doi.org/10.1038/s41467-018-07581-4

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

In: Nature Communications, Vol. 9, No. 1, 5457, 01.12.2018.

Research output: Contribution to journal › Article › peer-review

Brockmann, L, Soukou, S, Steglich, B, Czarnewski, P, Zhao, L, Wende, S, Bedke, T, Ergen, C, Manthey, C, Agalioti, T, Geffken, M, Seiz, O, Parigi, SM, Sorini, C, Geginat, J, Fujio, K, Jacobs, T, Roesch, T, Izbicki, JR, Lohse, AW, Flavell, RA, Krebs, C, Gustafsson, JA, Antonson, P, Roncarolo, MG, Villablanca, EJ, Gagliani, N & Huber, S 2018, ' Molecular and functional heterogeneity of IL-10-producing CD4 ⁺ T cells ', Nature Communications, vol. 9, no. 1, 5457. https://doi.org/10.1038/s41467-018-07581-4

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. / Molecular and functional heterogeneity of IL-10-producing CD4 ⁺ T cells In: Nature Communications. 2018 ; Vol. 9, No. 1.

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title = " Molecular and functional heterogeneity of IL-10-producing CD4 + T cells ",

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 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. ",

author = "Leonie Brockmann and Shiwa Soukou and Babett Steglich and Paulo Czarnewski and Lilan Zhao and Sandra Wende and Tanja Bedke and Can Ergen and Carolin Manthey and Theodora Agalioti and Maria Geffken and Oliver Seiz and Parigi, {Sara M.} and Chiara Sorini and Jens Geginat and Keishi Fujio and Thomas Jacobs and Thomas Roesch and Izbicki, {Jacob R.} and Lohse, {Ansgar W.} and Flavell, {Richard A.} and Christian Krebs and Gustafsson, {Jan Ake} and Per Antonson and Roncarolo, {Maria Grazia} and Villablanca, {Eduardo J.} and Nicola Gagliani and Samuel Huber",

note = "Funding Information: We thank the FACS Sorting Core Unit of the Universt{\"a}tsklinikum Hamburg{\"a}-Eppendorf for the excellent support. We are grateful to Prof. Stefan Kurtz at the Center for Bioinformatics of the University of Hamburg for providing access to the high-performance computing cluster. Jan-Ake Gustafsson is thankful to the Robert A Welch Foundation for a fellowship (E-0004). This work was supported by the DFG (SFB1192 to S.H., C.K., S.S.; SFB841 to S.H., N.G., A.W.L., T.J.; GA 2441/3-1 and HU 1714/10-1) and the ERC (to N.G. StG. 715271). S.H. was supported by the Stiftung Experimentelle Biomedizin and a Heisenberg Professorship. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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doi = "10.1038/s41467-018-07581-4",

language = "English (US)",

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T1 - Molecular and functional heterogeneity of IL-10-producing CD4 + T cells

AU - Brockmann, Leonie

AU - Soukou, Shiwa

AU - Steglich, Babett

AU - Czarnewski, Paulo

AU - Zhao, Lilan

AU - Wende, Sandra

AU - Bedke, Tanja

AU - Ergen, Can

AU - Manthey, Carolin

AU - Agalioti, Theodora

AU - Geffken, Maria

AU - Seiz, Oliver

AU - Parigi, Sara M.

AU - Sorini, Chiara

AU - Geginat, Jens

AU - Fujio, Keishi

AU - Jacobs, Thomas

AU - Roesch, Thomas

AU - Izbicki, Jacob R.

AU - Lohse, Ansgar W.

AU - Flavell, Richard A.

AU - Krebs, Christian

AU - Gustafsson, Jan Ake

AU - Antonson, Per

AU - Roncarolo, Maria Grazia

AU - Villablanca, Eduardo J.

AU - Gagliani, Nicola

AU - Huber, Samuel

N1 - Funding Information: We thank the FACS Sorting Core Unit of the Universtätsklinikum Hamburgä-Eppendorf for the excellent support. We are grateful to Prof. Stefan Kurtz at the Center for Bioinformatics of the University of Hamburg for providing access to the high-performance computing cluster. Jan-Ake Gustafsson is thankful to the Robert A Welch Foundation for a fellowship (E-0004). This work was supported by the DFG (SFB1192 to S.H., C.K., S.S.; SFB841 to S.H., N.G., A.W.L., T.J.; GA 2441/3-1 and HU 1714/10-1) and the ERC (to N.G. StG. 715271). S.H. was supported by the Stiftung Experimentelle Biomedizin and a Heisenberg Professorship. Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

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JF - Nat Commun

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

Abstract

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