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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.

Author information

1
INGM-National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy.
2
German Rheumatology Research Center DRFZ, Berlin, Germany.
3
Charitè Research Center for Immunosciences RCIS, Berlin, Germany.
4
Ospedale Pediatrico Bambino Gesù, Dipartimento Onco-Ematologia e Medicina Trasfusionale, Rome, Italy.
5
Unità Operativa di Gastroenterologia ed Endoscopia, Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
6
Department of Clinical Science and Community Health (DISCCO), University of Milan, Milan, Italy.
7
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.

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.

KEYWORDS:

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

PMID:
30431161
DOI:
10.1002/eji.201847722

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