Local administration of regulatory T cells promotes tissue healing
Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing.
Authors
- Daniela Amann‐Zalcenstein (ORCID: https://orcid.org/0000-0003-4928-1846)
- Yasmin K. Alshoubaki (ORCID: https://orcid.org/0000-0001-6031-531X)
- Nan Hu (ORCID: https://orcid.org/0009-0005-2565-0362)
- Shizuo Akira (ORCID: https://orcid.org/0000-0001-7602-9617)
- Xiaonong Wang
- Bhavana Nayer
- Ralph Müller (ORCID: https://orcid.org/0000-0002-5811-7725)
- Trevor Craig Wilson (ORCID: https://orcid.org/0000-0002-9026-0521)
- Ajithkumar Vasanthakumar (ORCID: https://orcid.org/0000-0002-1620-7781)
- Gisela Kuhn
- Julien M. D. Legrand (ORCID: https://orcid.org/0000-0001-5577-5645)
- Anthony Park (ORCID: https://orcid.org/0000-0002-5686-839X)
- Mikaël M. Martino (ORCID: https://orcid.org/0000-0002-5012-4605)
- Peter F. Hickey (ORCID: https://orcid.org/0000-0002-8153-6258)
- Jean L. Tan
- Yen‐Zhen Lu (ORCID: https://orcid.org/0000-0003-4262-3436)
- Sinnee Lau
Institutions
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- La Trobe University (AU)
- Australian Regenerative Medicine Institute (AU)
- ETH Zurich (CH)
- Institute for Biomedical Engineering (CH)
- Monash Health (AU)
- Olivia Newton-John Cancer Wellness & Research Centre (AU)
- Osaka International University (JP)
- Monash University (AU)
- Newcastle University (GB)
- The University of Osaka (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-09
- DOI
- https://doi.org/10.1038/s41467-024-51353-2
- Citations
- 66
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 15.87
Funders
- Sylvia and Charles Viertel Charitable Foundation
- Australian Government
- Monash University
- State Government of Victoria
- Medical Research Council
- National Health and Medical Research Council