The co-inhibitory receptor TIGIT promotes tissue-protective functions in T cells

nature immunology Article https://doi.org/10.1038/s41590-025-02300-w The co-inhibitory receptor TIGIT promotes tissue-protective functions in T cells Received: 19 November 2024 Accepted: 8 September 2025 Published online: 15 October 2025 Check for updates Camilla Panetti1, Rahel Daetwyler 1, Anja Moncsek 1, Nikolaos Patikas Andreas Agrafiotis3,4, Adelynn Tang5,6, Francesco Andreata 7,8, Valeria Fumagalli 7,8, Jean De Lima 9, Lifen Wen5, Carolyn G. King9, Ajithkumar Vasanthakumar 5,6,10,11, Matteo Iannacone 7,8, Axel Kallies Alexander Yermanos3,13,14, Martin Hemberg2 & Nicole Joller 1,15 , 2 , 5,12 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+ 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 (Treg) cells, but not CD8+ T cells, as the critical T cell subset mediating these tissue-protective effects. In Treg 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. Co-inhibitory receptors are essential for maintaining immune balance, preventing excessive immune activation and tissue damage under normal conditions and during inflammation1. T cell immunoglobulin and ITIM domain (TIGIT) is one of these co-inhibitory receptors, and it exerts its inhibitory function by directly inhibiting effector T cell activation as well as tolerizing dendritic cells through engagement of its ligand CD155 (refs. 2,3). Moreover, TIGIT is constitutively expressed on regulatory T (Treg) cells and enhances their suppressive capacity4. Loss of TIGIT results in increased susceptibility to autoimmunity, while promoting tumor clearance5. Similar to other co-inhibitory receptors, TIGIT is expressed after T cell activation, resulting in its upregulation during infections and sustained expression on exhausted T cells in chronic infections6,7. Interestingly, while TIGIT modulates the antiviral response following lymphocytic choriomeningitis virus (LCMV) infection, it does not alter viral control but rather limits the tissue pathology resulting from LCMV and influenza infection7. However, the underlying mechanism for this is still poorly understood. Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland. 2The Gene Lay Institute of Immunology and Inflammation of Brigham and Women’s Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA. 3Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. 4Institute of Microbiology, ETH Zurich, Zurich, Switzerland. 5Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia. 6La Trobe University, Bundoora, Victoria, Australia. 7Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. 8Vita-Salute San Raffaele University, Milan, Italy. 9 Department of Biomedicine, University of Basel, Basel, Switzerland. 10Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. 11 Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. 12Institute of Molecular Medicine & Experimental Immunology, University Hospital Bonn, Bonn, Germany. 13Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands. 14Botnar Institute of Immune Engineering, Basel, Switzerland. 15Center for Human Immunology, University of Zurich, Zurich, Switzerland. e-mail: 1 Nature Immunology | Volume 26 | November 2025 | 2074–2085 2074 Article https://doi.org/10.1038/s41590-025-02300-w 400 200 NS b **** 600 400 200 0 0 Naive LCMV Naive Percentage of Cas3+ 4 NS **** 150 NS NS 50 0 Naive WT 2 1 WT e ** NS 100 50 0 Naive d 3 Naive NS NS LCMV Tigit KO CD4+ 10 0 150 LCMV KO 200 µm Lung 200 **** **** 100 LCMV WT c Kidney 200 200 µm * 8 6 4 2 NS 8 6 4 2 0 0 WT KO LCMV CD8+ 10 Percentage of IFNγ+ 600 800 Evans blue (ng ml–1) **** Percentage of IFNγ+ NS AST (U l–1) AST (U l–1) 800 Evans blue (ng ml–1) a WT KO Tigit KO KO WT WT KO UMAP 2 56.38% 1.52% 0.11% 0.10% 14.53% 6.57% 0.13% 2.36% 0.79% 1.12% 12.25% 4.16% 47.60% 1.74% 0.29% 0.09% 18.82% 6.77% 0.18% 2.37% 1.84% 2.29% 11.44% 6.56% B cells NK cells NKT cells + TCRγδ T cells + CD8 T cells + – CD4 Foxp3 Tconv cells + + CD4 Foxp3 Treg cells Macrophages Monocytes DCs Neutrophils Other UMAP 1 Fig. 1 | Tigit-KO mice show increased tissue pathology following infection. WT and Tigit-KO mice were left naive or were infected with LCMV Cl13. a, AST and ALT levels in serum (data are shown as mean ∓ s.d.; pool of five independent experiments); NS, not significant. b, Colorimetric quantification of Evans Blue extravasation from kidney and lung (data are shown as mean ∓ s.d.; pool of two independent experiments) on day 10 postinfection. c, Quantification (left) and representative images (right) of caspase-3 (Cas3) staining as a marker of cellular apoptosis in infected liver sections (data are shown as mean ∓ s.d.; representative ROIs n = 19, 15, 23 and 20, biological replicates = 2–3). d, Frequencies of interferon-γ+CD4+ (IFNγ+CD4+) and IFNγ+CD8+ T cells following LCMV glycoprotein peptide restimulation at the peak of LCMV Cl13 infection in the spleen (data are shown as mean ∓ s.d.; pool of two to three independent experiments, n = 6 (CD4+) and n = 5 and 7 (CD8+)). Data were analyzed by twoway analysis of variance (ANOVA) with a Šídák’s post hoc test (a and c), two-way ANOVA with a Tukey’s post hoc test (b) or unpaired two-sided t-test (d). e, Uniform manifold approximation projections (UMAPs) and relative composition of immune cells in the spleen on day 7 after LCMV Cl13 infection; NK, natural killer; NKT, natural killer T cells; DCs, dendritic cells. In recent years, it has become increasingly evident that T cells, and Treg cells in particular, play a crucial role in maintaining tissue homeostasis by actively contributing to tissue regeneration and repair8. Treg cells accumulate at the site of tissue injury, and their depletion results in delayed tissue regeneration, exacerbated tissue damage and f (...truncated)