Eomesodermin controls a unique differentiation program in human IL-10 and IFN-γ coproducing regulatory T cells
Articolo
Data di Pubblicazione:
2019
Citazione:
Eomesodermin controls a unique differentiation program in human IL-10 and IFN-γ coproducing regulatory T cells / P. Gruarin, S. Maglie, M. De Simone, B. Häringer, C. Vasco, V. Ranzani, R. Bosotti, J.S. Noddings, P. Larghi, F. Facciotti, M.L. Sarnicola, M. Martinovic, M. Crosti, M. Moro, R.L. Rossi, M.E. Bernardo, F. Caprioli, F. Locatelli, G. Rossetti, S. Abrignani, M. Pagani, J. Geginat. - In: EUROPEAN JOURNAL OF IMMUNOLOGY. - ISSN 0014-2980. - 49:1(2019 Jan), pp. 96-111. [10.1002/eji.201847722]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Differentiation; EOMES; Granzyme K; Regulatory T cells; Th17
Elenco autori:
P. Gruarin, S. Maglie, M. De Simone, B. Häringer, C. Vasco, V. Ranzani, R. Bosotti, J.S. Noddings, P. Larghi, F. Facciotti, M.L. Sarnicola, M. Martinovic, M. Crosti, M. Moro, R.L. Rossi, M.E. Bernardo, F. Caprioli, F. Locatelli, G. Rossetti, S. Abrignani, M. Pagani, J. Geginat
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