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

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 cel...

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Published in:	European journal of immunology Vol. 49; no. 1; pp. 96 - 111
Main Authors:	Gruarin, Paola, Maglie, Stefano, 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
Format:	Journal Article
Language:	English
Published:	Germany Wiley Subscription Services, Inc 01-01-2019
Subjects:	Binding sites CD4 antigen CD40L protein Cell activation Cytotoxicity Dendritic cells Differentiation Effector cells EOMES Granzyme K Helper cells Immunological memory Immunoregulation Inflammatory bowel diseases Interferon Intestine Lymphocytes Lymphocytes T Memory cells Regulatory T cells T cell receptors Th17 EOMES Regulatory T cells Granzyme K Differentiation Th17
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Summary:	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. Eomes acts as a lineage‐defining transcription factor in human Tr1 cells. Human Tr1‐like cells express Eomesodermin (Eomes), which antagonizes Th17 differentiation and induces IFN‐γ, CCR5, and GzmK. Together with IL‐27, it promotes a switch from CD40L to IL‐10, and thus promotes regulatory and cytotoxic properties at the expense of helper functions.
Bibliography:	See accompanying Commentary by Dejean et al. These authors contributed equally to this work. https://onlinelibrary.wiley.com/doi/10.1002/eji.201848000 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0014-2980 1521-4141
DOI:	10.1002/eji.201847722