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Peer-reviewedCC BY 4.0Frontiers in Immunology

Regulatory T cell function and engineering for next generation cell therapies

  • Nathan W. Zammit1
  • Martina Sassone-Corsi1
  • Payam Zarin1
  • Tingxi Guo1
  • Maegan E. Hoover1
  • Marko Repic1
  • Gene I. Uenishi1
  • Christopher L. Moore1
  • Dalia Gaddis1
  • Mark A. Bach1
  • Chandra Patel1
  • Tiffany F. Chen1
1 more authors
  • Thomas J. Wickham1
  1. 1GentiBio Inc.
Open at sourceDOICite

Abstract

Regulatory T cells (Tregs) are essential for immune tolerance and tissue homeostasis. Their dysfunction contributes to a broad range of autoimmune, inflammatory, and degenerative diseases, motivating interest in Treg-based therapies. Clinical translation has been constrained by limited stability, persistence, and functional specialization, particularly within inflammatory tissue environments. Emerging evidence reveals that Tregs are not a uniform suppressive lineage but comprise tissue-adapted populations with distinct transcriptional, metabolic, and functional programs. These cells support organ integrity through mechanisms extending beyond immune regulation, including roles in tissue repair, metabolic tuning, and stem cell niche maintenance that significantly broadens their therapeutic potential. Here, we review established Treg biology and key learnings from select clinical experiences using unmodified Tregs. From there, we discuss the mechanisms and challenges limiting efficacy of Tregs, and present how the state-of-the-art engineering aims to enhance Treg durability, stability, and specificity. Finally, we conclude with a forward-looking perspective on how the future of Tregs can expand beyond immune suppression by incorporating recently discovered tissue-specific functions for next-generation therapies targeting a broad range of indications.

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Cite

BibTeXRIS
BibTeX
@article{zammit2026regulatory,
  title = {{Regulatory T cell function and engineering for next generation cell therapies}},
  author = {Nathan W. Zammit and Martina Sassone-Corsi and Payam Zarin and Tingxi Guo and Maegan E. Hoover and Marko Repic and Gene I. Uenishi and Christopher L. Moore and Dalia Gaddis and Mark A. Bach and Chandra Patel and Tiffany F. Chen and Thomas J. Wickham},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1887951},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1887951/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Regulatory T cell function and engineering for next generation cell therapies
AU  - Nathan W. Zammit
AU  - Martina Sassone-Corsi
AU  - Payam Zarin
AU  - Tingxi Guo
AU  - Maegan E. Hoover
AU  - Marko Repic
AU  - Gene I. Uenishi
AU  - Christopher L. Moore
AU  - Dalia Gaddis
AU  - Mark A. Bach
AU  - Chandra Patel
AU  - Tiffany F. Chen
AU  - Thomas J. Wickham
PY  - 2026
DA  - 2026/10/19
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1887951
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1887951/full
AB  - Regulatory T cells (Tregs) are essential for immune tolerance and tissue homeostasis. Their dysfunction contributes to a broad range of autoimmune, inflammatory, and degenerative diseases, motivating interest in Treg-based therapies. Clinical translation has been constrained by limited stability, persistence, and functional specialization, particularly within inflammatory tissue environments. Emerging evidence reveals that Tregs are not a uniform suppressive lineage but comprise tissue-adapted populations with distinct transcriptional, metabolic, and functional programs. These cells support organ integrity through mechanisms extending beyond immune regulation, including roles in tissue repair, metabolic tuning, and stem cell niche maintenance that significantly broadens their therapeutic potential. Here, we review established Treg biology and key learnings from select clinical experiences using unmodified Tregs. From there, we discuss the mechanisms and challenges limiting efficacy of Tregs, and present how the state-of-the-art engineering aims to enhance Treg durability, stability, and specificity. Finally, we conclude with a forward-looking perspective on how the future of Tregs can expand beyond immune suppression by incorporating recently discovered tissue-specific functions for next-generation therapies targeting a broad range of indications.
SN  - 1664-3224
ER  -