Eomesodermin controls a unique differentiation program in human IL‐10 and IFN‐γ coproducing regulatory T cells
Open accessAbstract
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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T-bet is expressed at high levels in CD4+ CTL, but only at a lower level in Th1 memory cells.
“T-bet is expressed at high levels in CD4+ CTL [169], but only at a lower level in Th1 memory cells.”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [169]
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How the Immune System Responds to Allergy Immunotherapy
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- Authors
- Gruarin, P., Maglie, S., De Simone, M., Häringer, B., Vasco, C., Ranzani, V., Bosotti, R., Noddings, J. S., Larghi, P., Facciotti, F., Sarnicola, M. L., Martinovic, M., Crosti, M., Moro, M., Rossi, R. L., Bernardo, M. E., Caprioli, F., Locatelli, F., Rossetti, G., Abrignani, S., Pagani, M., & Geginat, J.
- Affiliations
- Istituto Nazionale Genetica Molecolare (IT)
- INGM‐National Institute of Molecular Genetics “Romeo ed Enrica Invernizzi” Milan Italy
- German Rheumatism Research Centre (DE)
- Bambino Gesù Children's Hospital (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- University of Milan (IT)
- Corresponding author
- Geginat, Jens
- ORCID
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 2018-11-29
- Volume
- 49
- Issue
- 1
- Pages
- 96-111
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W2901980385
- Cited by
- 92
- References
- 50
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 14 · 2023: 16 · 2022: 18 · 2021: 12 · 2020: 5 · 2019: 12 · 2018: 2
- FWCI
- 3.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
- BOA (University of Milano-Bicocca) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- Associazione Italiana per la Ricerca sul Cancro (IG 2015 Id17448)
- Fondazione Cariplo (2013‐0937)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- Eomesodermin, regulatory T cells, IL-10, interferon-gamma, granzyme K, CD4+ T cell differentiation, transcription factors, IL-4, IL-12, dendritic cells, IL-27, CD40 ligand, IL-7 receptor, inflammatory bowel disease, graft-versus-host disease, effector memory T cells
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Gene Expression Regulation, Graft vs Host Disease, Humans, Immunologic Memory, Interferon-gamma, Inflammatory Bowel Diseases, T-Lymphocyte Subsets, Interleukin-10, Th1 Cells, Cell Lineage, T-Box Domain Proteins, T-Lymphocytes, Regulatory, Mice, Granzymes
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