Eomesodermin controls a unique differentiation program in human IL-10 and IFN-γ coproducing regulatory T cells

Paola Gruarin, Stefano Maglie, Marco De Simone, Barbara Häringer, Chiara Vasco, Valeria Ranzani, Roberto Bosotti, Johanna S Noddings, Paola Larghi, Federica Facciotti, Maria L Sarnicola, Martina Martinovic, Mariacristina Crosti, Monica Moro, Riccardo L Rossi, Maria E Bernardo, Flavio Caprioli, Franco Locatelli, Grazisa Rossetti, Sergio AbrignaniMassimiliano Pagani, Jens Geginat

Research output: Contribution to journalArticle

Abstract

Whether human IL-10-producing regulatory T cells ("Tr1") represent a distinct differentiation lineage or an unstable activation stage remains a key unsolved issue. Here, we report that Eomesodermin (Eomes) acted as a lineage-defining transcription factor in human IFN-γ/IL-10 coproducing Tr1-like cells. In vivo occurring Tr1-like cells expressed Eomes, and were clearly distinct from all other CD4+ T-cell subsets, including conventional cytotoxic CD4+ T cells. They expressed Granzyme (Gzm) K, but had lost CD40L and IL-7R expression. Eomes antagonized the Th17 fate, and directly controlled IFN-γ and GzmK expression. However, Eomes binding to the IL-10 promoter was not detectable in human CD4+ T cells, presumably because critical Tbox binding sites of the mouse were not conserved. A precommitment to a Tr1-like fate, i.e. concominant induction of Eomes, GzmK, and IFN-γ, was promoted by IL-4 and IL-12-secreting myeloid dendritic cells. Consistently, Th1 effector memory cells contained precommitted Eomes+ GzmK+ T cells. Stimulation with T-cell receptor (TCR) agonists and IL-27 promoted the generation of Tr1-like effector cells by inducing switching from CD40L to IL-10. Importantly, CD4+ Eomes+ T-cell subsets were present in lymphoid and nonlymphoid tissues, and their frequencies varied systemically in patients with inflammatory bowel disease and graft-versus-host disease. We propose that Eomes+ Tr1-like cells are effector cells of a unique GzmK-expressing CD4+ T-cell subset.

Original languageEnglish
Number of pages16
JournalEuropean Journal of Immunology
DOIs
Publication statusE-pub ahead of print - Nov 15 2018

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Regulatory T-Lymphocytes
Interleukin-10
T-Lymphocyte Subsets
CD40 Ligand
T-Lymphocytes
Interleukin-27
Granzymes
Lymphoid Tissue
Graft vs Host Disease
Myeloid Cells
Interleukin-12
T-Cell Antigen Receptor
Inflammatory Bowel Diseases
Interleukin-4
Dendritic Cells
Transcription Factors
Binding Sites

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Eomesodermin controls a unique differentiation program in human IL-10 and IFN-γ coproducing regulatory T cells. / Gruarin, Paola; Maglie, Stefano; De Simone, Marco; Häringer, Barbara; Vasco, Chiara; Ranzani, Valeria; Bosotti, Roberto; Noddings, Johanna S; Larghi, Paola; Facciotti, Federica; Sarnicola, Maria L; Martinovic, Martina; Crosti, Mariacristina; Moro, Monica; Rossi, Riccardo L; Bernardo, Maria E; Caprioli, Flavio; Locatelli, Franco; Rossetti, Grazisa; Abrignani, Sergio; Pagani, Massimiliano; Geginat, Jens.

In: European Journal of Immunology, 15.11.2018.

Research output: Contribution to journalArticle

Gruarin, P, Maglie, S, De Simone, M, Häringer, B, Vasco, C, Ranzani, V, Bosotti, R, Noddings, JS, Larghi, P, Facciotti, F, Sarnicola, ML, Martinovic, M, Crosti, M, Moro, M, Rossi, RL, Bernardo, ME, Caprioli, F, Locatelli, F, Rossetti, G, Abrignani, S, Pagani, M & Geginat, J 2018, 'Eomesodermin controls a unique differentiation program in human IL-10 and IFN-γ coproducing regulatory T cells', European Journal of Immunology. https://doi.org/10.1002/eji.201847722
Gruarin, Paola ; Maglie, Stefano ; De Simone, Marco ; Häringer, Barbara ; Vasco, Chiara ; Ranzani, Valeria ; Bosotti, Roberto ; Noddings, Johanna S ; Larghi, Paola ; Facciotti, Federica ; Sarnicola, Maria L ; Martinovic, Martina ; Crosti, Mariacristina ; Moro, Monica ; Rossi, Riccardo L ; Bernardo, Maria E ; Caprioli, Flavio ; Locatelli, Franco ; Rossetti, Grazisa ; Abrignani, Sergio ; Pagani, Massimiliano ; Geginat, Jens. / Eomesodermin controls a unique differentiation program in human IL-10 and IFN-γ coproducing regulatory T cells. In: European Journal of Immunology. 2018.
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abstract = "Whether human IL-10-producing regulatory T cells ({"}Tr1{"}) represent a distinct differentiation lineage or an unstable activation stage remains a key unsolved issue. Here, we report that Eomesodermin (Eomes) acted as a lineage-defining transcription factor in human IFN-γ/IL-10 coproducing Tr1-like cells. In vivo occurring Tr1-like cells expressed Eomes, and were clearly distinct from all other CD4+ T-cell subsets, including conventional cytotoxic CD4+ T cells. They expressed Granzyme (Gzm) K, but had lost CD40L and IL-7R expression. Eomes antagonized the Th17 fate, and directly controlled IFN-γ and GzmK expression. However, Eomes binding to the IL-10 promoter was not detectable in human CD4+ T cells, presumably because critical Tbox binding sites of the mouse were not conserved. A precommitment to a Tr1-like fate, i.e. concominant induction of Eomes, GzmK, and IFN-γ, was promoted by IL-4 and IL-12-secreting myeloid dendritic cells. Consistently, Th1 effector memory cells contained precommitted Eomes+ GzmK+ T cells. Stimulation with T-cell receptor (TCR) agonists and IL-27 promoted the generation of Tr1-like effector cells by inducing switching from CD40L to IL-10. Importantly, CD4+ Eomes+ T-cell subsets were present in lymphoid and nonlymphoid tissues, and their frequencies varied systemically in patients with inflammatory bowel disease and graft-versus-host disease. We propose that Eomes+ Tr1-like cells are effector cells of a unique GzmK-expressing CD4+ T-cell subset.",
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T1 - Eomesodermin controls a unique differentiation program in human IL-10 and IFN-γ coproducing regulatory T cells

AU - Gruarin, Paola

AU - Maglie, Stefano

AU - De Simone, Marco

AU - Häringer, Barbara

AU - Vasco, Chiara

AU - Ranzani, Valeria

AU - Bosotti, Roberto

AU - Noddings, Johanna S

AU - Larghi, Paola

AU - Facciotti, Federica

AU - Sarnicola, Maria L

AU - Martinovic, Martina

AU - Crosti, Mariacristina

AU - Moro, Monica

AU - Rossi, Riccardo L

AU - Bernardo, Maria E

AU - Caprioli, Flavio

AU - Locatelli, Franco

AU - Rossetti, Grazisa

AU - Abrignani, Sergio

AU - Pagani, Massimiliano

AU - Geginat, Jens

N1 - © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2018/11/15

Y1 - 2018/11/15

N2 - Whether human IL-10-producing regulatory T cells ("Tr1") represent a distinct differentiation lineage or an unstable activation stage remains a key unsolved issue. Here, we report that Eomesodermin (Eomes) acted as a lineage-defining transcription factor in human IFN-γ/IL-10 coproducing Tr1-like cells. In vivo occurring Tr1-like cells expressed Eomes, and were clearly distinct from all other CD4+ T-cell subsets, including conventional cytotoxic CD4+ T cells. They expressed Granzyme (Gzm) K, but had lost CD40L and IL-7R expression. Eomes antagonized the Th17 fate, and directly controlled IFN-γ and GzmK expression. However, Eomes binding to the IL-10 promoter was not detectable in human CD4+ T cells, presumably because critical Tbox binding sites of the mouse were not conserved. A precommitment to a Tr1-like fate, i.e. concominant induction of Eomes, GzmK, and IFN-γ, was promoted by IL-4 and IL-12-secreting myeloid dendritic cells. Consistently, Th1 effector memory cells contained precommitted Eomes+ GzmK+ T cells. Stimulation with T-cell receptor (TCR) agonists and IL-27 promoted the generation of Tr1-like effector cells by inducing switching from CD40L to IL-10. Importantly, CD4+ Eomes+ T-cell subsets were present in lymphoid and nonlymphoid tissues, and their frequencies varied systemically in patients with inflammatory bowel disease and graft-versus-host disease. We propose that Eomes+ Tr1-like cells are effector cells of a unique GzmK-expressing CD4+ T-cell subset.

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