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Regulatory T cell and endothelial cell crosstalk

Nature Reviews Immunology volume 25, pages 588–607 (2025)Cite this article

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Abstract

Regulatory T (Treg) cells have a central role in the maintenance of immune surveillance and tolerance. They can migrate from lymphoid organs to blood and then into tissues and egress from tissues into draining lymph nodes. Specialized endothelial cells of blood and lymphatic vessels are the key gatekeepers for these processes. Treg cells that transmigrate across single-cell layers of endothelial cells engage in bidirectional crosstalk with these cells and regulate vascular permeability by promoting structural modifications of blood and lymphatic endothelial cells. In turn, blood and lymphatic endothelial cells can modulate Treg cell recirculation and residency. Here, we discuss recent insights into the cellular and molecular mechanisms of the crosstalk between Treg cells and endothelial cells and explore potential therapeutic strategies to target these interactions in autoimmunity, transplantation and cancer.

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Fig. 1: Treg cell trafficking by direct interaction with endothelium.
Fig. 2: Role of LTα1β2–LTβR in Treg cell migration.
Fig. 3: Role of S1P and S1PRs in Treg cell migration.
Fig. 4: Role of PD1 and PDL1 in Treg cell migration.
Fig. 5: Treg cell migration to and from tumours.
Fig. 6: Endothelial cells directly affect Treg cell function and stability.

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Acknowledgements

This work was supported in part by NIH R37 AI062765 to J.S.B.; Emerald grant 2022 to J.S.B. and W.P.; NIH # R01AI169686 and VA # I01BX003690 to C.M.J.

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Authors and Affiliations

  1. Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA

    Wenji Piao, Zachariah L. Lee, Gregory Zapas, Long Wu & Jonathan S. Bromberg

  2. Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA

    Wenji Piao, Long Wu & Jonathan S. Bromberg

  3. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA

    Christopher M. Jewell & Jonathan S. Bromberg

  4. Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA

    Christopher M. Jewell

  5. Department of Veterans Affairs, VA Maryland Health Care System, Baltimore, MD, USA

    Christopher M. Jewell

  6. Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Reza Abdi

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W.P. and J.S.B. researched data for the article. All authors reviewed and/or edited the manuscript before submission.

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Competing interests

C.M.J. is an employee of the VA Maryland Health Care System. The views reported in this article do not reflect the views of the Department of Veterans Affairs or the United States Government. C.M.J. has an equity position with Barinthus Biotherapeutics and Cartesian Therapeutics. The other authors declare no competing interests.

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Piao, W., Lee, Z.L., Zapas, G. et al. Regulatory T cell and endothelial cell crosstalk. Nat Rev Immunol 25, 588–607 (2025). https://doi.org/10.1038/s41577-025-01149-2

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