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Eur J Immunol. 2019 Jan;49(1):96-111. doi: 10.1002/eji.201847722. Epub 2018 Nov 29.

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

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INGM-National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy.
German Rheumatology Research Center DRFZ, Berlin, Germany.
Charitè Research Center for Immunosciences RCIS, Berlin, Germany.
Ospedale Pediatrico Bambino Gesù, Dipartimento Onco-Ematologia e Medicina Trasfusionale, Rome, Italy.
Unità Operativa di Gastroenterologia ed Endoscopia, Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Department of Clinical Science and Community Health (DISCCO), University of Milan, Milan, Italy.
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.


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.


Differentiation; EOMES; Granzyme K; Regulatory T cells; Th17


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