The co-inhibitory receptor TIGIT promotes tissue-protective functions in T cells
The co-inhibitory receptor TIGIT suppresses excessive immune responses in autoimmune conditions while also restraining antitumor immunity. In viral infections, TIGIT alone does not affect viral control but has been shown to limit tissue pathology. However, the underlying mechanisms are incompletely understood. Here we found TIGIT<sup>+</sup> T cells to express not only an immunoregulatory gene signature but also a tissue repair gene signature. Specifically, after viral infection, TIGIT directly drives expression of the tissue growth factor amphiregulin (Areg), which is strongly reduced in the absence of TIGIT. We identified regulatory T (T<sub>reg</sub>) cells, but not CD8<sup>+</sup> T cells, as the critical T cell subset mediating these tissue-protective effects. In T<sub>reg</sub> cells, TIGIT engagement after T cell antigen receptor stimulation induces the transcription factor Blimp-1, which then promotes Areg production and tissue repair. Thus, we uncovered a nonclassical function of the co-inhibitory receptor TIGIT, wherein it not only limits immune pathology by suppressing the immune response but also actively fosters tissue regeneration by inducing the tissue growth factor Areg in T cells.
Authors
- J. Lima (ORCID: https://orcid.org/0009-0002-2264-7107)
- Francesco Andreata (ORCID: https://orcid.org/0000-0002-5710-3671)
- Axel Kallies (ORCID: https://orcid.org/0000-0002-6312-6968)
- Lifen Wen (ORCID: https://orcid.org/0000-0003-0229-7306)
- Valeria Fumagalli (ORCID: https://orcid.org/0000-0003-2583-2498)
- Carolyn G. King (ORCID: https://orcid.org/0000-0001-6059-323X)
- Andreas Agrafiotis (ORCID: https://orcid.org/0000-0003-0797-4695)
- Camilla Panetti
- Anja Moncsek (ORCID: https://orcid.org/0000-0002-1191-5842)
- Ajithkumar Vasanthakumar (ORCID: https://orcid.org/0000-0002-1620-7781)
- Alexander Yermanos (ORCID: https://orcid.org/0000-0001-6238-0588)
- Matteo Iannacone (ORCID: https://orcid.org/0000-0002-9370-2671)
- Nicole Joller (ORCID: https://orcid.org/0000-0003-1996-1672)
- Nikolaos Patikas (ORCID: https://orcid.org/0000-0002-3978-0134)
- Martin Hemberg (ORCID: https://orcid.org/0000-0001-8452-268X)
- Adelynn Tang (ORCID: https://orcid.org/0000-0001-8256-6013)
- Rahel Daetwyler
Institutions
- Brigham and Women's Hospital (US)
- Union Bank of Switzerland (CH)
- Harvard University (US)
- Vita-Salute San Raffaele University (IT)
- The University of Melbourne (AU)
- University of Basel (CH)
- La Trobe University (AU)
- University of Zurich (CH)
- University Hospital Bonn (DE)
- Peter MacCallum Cancer Centre (AU)
- University Medical Center Utrecht (NL)
- ETH Zurich (CH)
- Massachusetts General Hospital (US)
- Peter Doherty Institute (AU)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Olivia Newton-John Cancer Wellness & Research Centre (AU)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
Publication Details
- Journal
- Nature Immunology
- Published
- 2025-10-15
- DOI
- https://doi.org/10.1038/s41590-025-02300-w
- Citations
- 8
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 6.38
Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council