Terminal differentiation and persistence of effector regulatory T cells essential for preventing intestinal inflammation

Stanislav Dikiy; Aazam P. Ghelani; Andrew G. Levine; Stephen Martis; Paolo Giovanelli; Zhong Min Wang; Giorgi Beroshvili; Yuri Pritykin; Chirag Krishna; Xiao Huang; Ariella Glasner; Benjamin D. Greenbaum; Christina S. Leslie; Alexander Y. Rudensky

doi:10.1038/s41590-024-02075-6

Terminal differentiation and persistence of effector regulatory T cells essential for preventing intestinal inflammation

Stanislav Dikiy, Aazam P. Ghelani, Andrew G. Levine, Stephen Martis, Paolo Giovanelli, Zhong Min Wang, Giorgi Beroshvili, Yuri Pritykin, Chirag Krishna, Xiao Huang, Ariella Glasner, Benjamin D. Greenbaum, Christina S. Leslie, Alexander Y. Rudensky

Research output: Contribution to journal › Article › peer-review

Abstract

Regulatory T (T_reg) cells are a specialized CD4⁺ T cell lineage with essential anti-inflammatory functions. Analysis of T_reg cell adaptations to non-lymphoid tissues that enable their specialized immunosuppressive and tissue-supportive functions raises questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Here, we characterize distinct colonic effector T_reg cell transcriptional programs. Attenuated T cell receptor (TCR) signaling and acquisition of substantial TCR-independent functionality seems to facilitate the terminal differentiation of a population of colonic effector T_reg cells that are distinguished by stable expression of the immunomodulatory cytokine IL-10. Functional studies show that this subset of effector T_reg cells, but not their expression of IL-10, is indispensable for colonic health. These findings identify core features of the terminal differentiation of effector T_reg cells in non-lymphoid tissues and their function.

Original language	American English
Article number	e40553
Pages (from-to)	444-458
Number of pages	15
Journal	Nature Immunology
Volume	26
Issue number	3
DOIs	https://doi.org/10.1038/s41590-024-02075-6
State	Published - Mar 2025
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1038/s41590-024-02075-6

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Dikiy, S., Ghelani, A. P., Levine, A. G., Martis, S., Giovanelli, P., Wang, Z. M., Beroshvili, G., Pritykin, Y., Krishna, C., Huang, X., Glasner, A., Greenbaum, B. D., Leslie, C. S., & Rudensky, A. Y. (2025). Terminal differentiation and persistence of effector regulatory T cells essential for preventing intestinal inflammation. Nature Immunology, 26(3), 444-458. Article e40553. https://doi.org/10.1038/s41590-024-02075-6

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title = "Terminal differentiation and persistence of effector regulatory T cells essential for preventing intestinal inflammation",

abstract = "Regulatory T (Treg) cells are a specialized CD4+ T cell lineage with essential anti-inflammatory functions. Analysis of Treg cell adaptations to non-lymphoid tissues that enable their specialized immunosuppressive and tissue-supportive functions raises questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Here, we characterize distinct colonic effector Treg cell transcriptional programs. Attenuated T cell receptor (TCR) signaling and acquisition of substantial TCR-independent functionality seems to facilitate the terminal differentiation of a population of colonic effector Treg cells that are distinguished by stable expression of the immunomodulatory cytokine IL-10. Functional studies show that this subset of effector Treg cells, but not their expression of IL-10, is indispensable for colonic health. These findings identify core features of the terminal differentiation of effector Treg cells in non-lymphoid tissues and their function.",

author = "Stanislav Dikiy and Ghelani, {Aazam P.} and Levine, {Andrew G.} and Stephen Martis and Paolo Giovanelli and Wang, {Zhong Min} and Giorgi Beroshvili and Yuri Pritykin and Chirag Krishna and Xiao Huang and Ariella Glasner and Greenbaum, {Benjamin D.} and Leslie, {Christina S.} and Rudensky, {Alexander Y.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = mar,

doi = "10.1038/s41590-024-02075-6",

language = "American English",

volume = "26",

pages = "444--458",

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Dikiy, S, Ghelani, AP, Levine, AG, Martis, S, Giovanelli, P, Wang, ZM, Beroshvili, G, Pritykin, Y, Krishna, C, Huang, X, Glasner, A, Greenbaum, BD, Leslie, CS & Rudensky, AY 2025, 'Terminal differentiation and persistence of effector regulatory T cells essential for preventing intestinal inflammation', Nature Immunology, vol. 26, no. 3, e40553, pp. 444-458. https://doi.org/10.1038/s41590-024-02075-6

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AU - Ghelani, Aazam P.

AU - Levine, Andrew G.

AU - Martis, Stephen

AU - Giovanelli, Paolo

AU - Wang, Zhong Min

AU - Beroshvili, Giorgi

AU - Pritykin, Yuri

AU - Krishna, Chirag

AU - Huang, Xiao

AU - Glasner, Ariella

AU - Greenbaum, Benjamin D.

AU - Leslie, Christina S.

AU - Rudensky, Alexander Y.

PY - 2025/3

Y1 - 2025/3

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AB - Regulatory T (Treg) cells are a specialized CD4+ T cell lineage with essential anti-inflammatory functions. Analysis of Treg cell adaptations to non-lymphoid tissues that enable their specialized immunosuppressive and tissue-supportive functions raises questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Here, we characterize distinct colonic effector Treg cell transcriptional programs. Attenuated T cell receptor (TCR) signaling and acquisition of substantial TCR-independent functionality seems to facilitate the terminal differentiation of a population of colonic effector Treg cells that are distinguished by stable expression of the immunomodulatory cytokine IL-10. Functional studies show that this subset of effector Treg cells, but not their expression of IL-10, is indispensable for colonic health. These findings identify core features of the terminal differentiation of effector Treg cells in non-lymphoid tissues and their function.

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Terminal differentiation and persistence of effector regulatory T cells essential for preventing intestinal inflammation

Abstract

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