Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

CD160+ intraepithelial lymphocytes and CCRL2+ macrophages drive differential repair in cardiac and liver injuries

Cellular & Molecular Immunology volume 23, pages 186–203 (2026)Cite this article

Subjects

Abstract

The regenerative capacities of organs in adult mammals vary significantly. Unlike the liver, which possesses remarkable regenerative potential, the repair of cardiac injuries has long posed a critical medical challenge. Recent studies have highlighted the pivotal role of the immune microenvironment in repairing damage in these tissues, but the key cell types and their mechanisms of action remain incompletely understood. In this study, we established a model of concurrent physical trauma to the hearts and livers of adult mice, revealing that these two injured tissues drive distinct immune microenvironments. The liver primarily accumulates lymphocytes, whereas the heart recruits macrophages and neutrophils. Notably, CD160+CD8+ intraepithelial lymphocytes in the liver were found to suppress fibrosis postliver injury and mitigate cardiac fibrosis when delivered via hydrogel patches. Conversely, in response to heart trauma, recruited inflammatory macrophages not only express proinflammatory cytokines but also coexpress CCRL2. While CCRL2 did not directly alter the intensity of the inflammatory response, it facilitated fibroblast proliferation and migration through its interaction with Na+/K+-ATPase on fibroblasts. These findings elucidated the contrasting immune microenvironments between the heart and liver following injury and provided novel insights and strategies for diagnosing and treating cardiac diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Immune microenvironment dominance of myeloid cells in the heart and lymphocytes in the liver following injury.
Fig. 2: The crucial role of CD160+CD8+ intraepithelial lymphocytes in tissue repair following injury.
Fig. 3: CCRL2+ inflammatory cardiac macrophages accumulate in the fibrotic area postinjury.
Fig. 4: Restoration of cardiac injury repair and fibrosis in the absence of CCRL2.
Fig. 5: CCRL2 has no intrinsic role in the inflammatory response after cardiac injury.
Fig. 6: CCRL2 promoted the proliferation and activation of cardiac fibroblasts.
Fig. 7: CCRL2 activates cardiac fibroblasts by interacting with Na+/K+-ATPase.

Similar content being viewed by others

References

  1. Eming SA, Wynn TA, Martin P. Inflammation and metabolism in tissue repair and regeneration. Science. 2017;356:1026–30.

    Article  CAS  PubMed  Google Scholar 

  2. Baddour JA, Sousounis K, Tsonis PA. Organ repair and regeneration: an overview. Birth Defects Res Part C Embryo Today Rev. 2012;96:1–29.

    Article  CAS  Google Scholar 

  3. Campana L, Esser H, Huch M, Forbes S. Liver regeneration and inflammation: from fundamental science to clinical applications. Nat Rev Mol Cell Biol. 2021;22:608–24.

    Article  CAS  PubMed  Google Scholar 

  4. Michalopoulos GK, Bhushan B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol. 2021;18:40–55.

    Article  PubMed  Google Scholar 

  5. Kim W, et al. Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis. J Clin Investig. 2017;127:137–52.

    Article  PubMed  Google Scholar 

  6. Huang R, Zhang X, Gracia-Sancho J, Xie W-F. Liver regeneration: cellular origin and molecular mechanisms. Liver Int. 2022;42:1486–95.

    Article  CAS  PubMed  Google Scholar 

  7. Hoffmann K, et al. Markers of liver regeneration-the role of growth factors and cytokines: a systematic review. BMC Surg. 2020;20:31.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Zhang C, Sun C, Zhao Y, Ye B, Yu G. Signaling pathways of liver regeneration: biological mechanisms and implications. iScience. 2024;27:108683.

    Article  CAS  PubMed  Google Scholar 

  9. Hora S, Wuestefeld T. Liver injury and regeneration: current understanding, new approaches, and future perspectives. Cells 2023;12:2129.

  10. Nguyen-Lefebvre AT, et al. Modeling the liver’s regenerative capacity across different clinical conditions. JHEP Rep Innov Hepatol. 2025;7:101465.

    Article  Google Scholar 

  11. Cahill TJ, Choudhury RP, Riley PR. Heart regeneration and repair after myocardial infarction: translational opportunities for novel therapeutics. Nat Rev Drug Discov. 2017;16:699–717.

    Article  CAS  PubMed  Google Scholar 

  12. Lerman DA, Alotti N, Ume KL, Péault B. Cardiac repair and regeneration: the value of cell therapies. Eur Cardiol. 2016;11:43–48.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Frangogiannis NG. The extracellular matrix in myocardial injury, repair, and remodeling. J Clin Investig. 2017;127:1600–12.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Xue M, Jackson CJ. Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care. 2015;4:119–36.

    Article  Google Scholar 

  15. Schütte JP, et al. Cell type–specific secretome analysis reveals liver-heart crosstalk in HFpEF. Circ Res. 2025;136:1516–8.

    Article  PubMed  Google Scholar 

  16. Sun H, et al. Cirrhosis promotes cardiac fibrosis development by inhibiting Notch1 in cardiac fibroblasts. JACC Basic Transl Sci. 2025;10:612–31.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Gieseck RL, Wilson MS, Wynn TA. Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol. 2018;18:62–76.

    Article  CAS  PubMed  Google Scholar 

  18. Julier Z, Park AJ, Briquez PS, Martino MM. Promoting tissue regeneration by modulating the immune system. Acta Biomater. 2017;53:13–28.

    Article  CAS  PubMed  Google Scholar 

  19. Rurik JG, Aghajanian H, Epstein JA. Immune cells and immunotherapy for cardiac injury and repair. Circ Res. 2021;128:1766–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Epelman S, Liu PP, Mann DL. Role of innate and adaptive immune mechanisms in cardiac injury and repair. Nat Rev Immunol. 2015;15:117–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yap J, et al. Macrophages in cardiac remodeling after myocardial infarction. Nat Rev Cardiol. 2023;20:373–85.

    Article  PubMed  Google Scholar 

  22. de Couto G. Macrophages in cardiac repair: environmental cues and therapeutic strategies. Exp Mol Med. 2019;51:1–10.

    Article  PubMed  Google Scholar 

  23. Yu Y, et al. Macrophages play a key role in tissue repair and regeneration. PeerJ. 2022;10:e14053.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14:181–94.

    Article  CAS  PubMed  Google Scholar 

  25. Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017;17:306–21.

    Article  CAS  PubMed  Google Scholar 

  26. Crispe IN. Hepatic T cells and liver tolerance. Nat Rev Immunol. 2003;3:51–62.

    Article  CAS  PubMed  Google Scholar 

  27. Gao B, Radaeva S, Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J Leukoc Biol. 2009;86:513–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gomes RN, Manuel F, Nascimento DS. The bright side of fibroblasts: molecular signature and regenerative cues in major organs. npj Regen Med. 2021;6:43.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol. 2021;18:151–66.

    Article  PubMed  Google Scholar 

  30. Ivey MJ, Tallquist MD. Defining the cardiac fibroblast. Circ J. 2016;80:2269–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Van Linthout S, Miteva K, Tschöpe C. Crosstalk between fibroblasts and inflammatory cells. Cardiovasc Res. 2014;102:258–69.

    Article  PubMed  Google Scholar 

  32. Huang E, et al. The roles of immune cells in the pathogenesis of fibrosis. Int J Mol Sci. 2020;21:5203.

  33. Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis. 2010;30:245–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Budi EH, Schaub JR, Decaris M, Turner S, Derynck R. TGF-β as a driver of fibrosis: physiological roles and therapeutic opportunities. J Pathol. 2021;254:358–73.

    Article  CAS  PubMed  Google Scholar 

  35. Waterhouse NJ, et al. A central role for bid in granzyme B-induced apoptosis *. J Biol Chem. 2005;280:4476–82.

    Article  CAS  PubMed  Google Scholar 

  36. Velotti F, Barchetta I, Cimini FA, Cavallo MG. Granzyme B in inflammatory diseases: apoptosis, inflammation, extracellular matrix remodeling, epithelial-to-mesenchymal transition and fibrosis. Front Immunol. 2020;11:587581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Epelman S, et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity. 2014;40:91–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li G, et al. Optogenetic vagal nerve stimulation attenuates heart failure by limiting the generation of monocyte-derived inflammatory CCRL2+ macrophages. Immunity. 2025;58:1847–1861.e1849.

    Article  CAS  PubMed  Google Scholar 

  39. McLellan MA, et al. High-resolution transcriptomic profiling of the heart during chronic stress reveals cellular drivers of cardiac fibrosis and hypertrophy. Circulation. 2020;142:1448–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pierre SV, Xie Z. The Na,K-ATPase receptor complex. Cell Biochem Biophys. 2006;46:303–15.

    Article  CAS  PubMed  Google Scholar 

  41. Shoshani L, et al. The polarized expression of Na+,K+-ATPase in epithelia depends on the association between β-subunits located in neighboring cells. Mol Biol Cell. 2005;16:1071–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tokhtaeva E, et al. Epithelial junctions depend on intercellular trans-interactions between the Na,K-ATPase β₁ subunits. J Biol Chem. 2011;286:25801–12.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Rajasekaran SA, et al. Na-K-ATPase regulates tight junction permeability through occludin phosphorylation in pancreatic epithelial cells. Am J Physiol-Gastrointest Liver Physiol. 2007;292:G124–G133.

    Article  CAS  PubMed  Google Scholar 

  44. Rajasekaran SA, et al. Na,K-ATPase activity is required for formation of tight junctions, desmosomes, and induction of polarity in epithelial cells. Mol Biol Cell. 2001;12:3717–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rajasekaran SA, Rajasekaran AK. Na,K-ATPase and epithelial tight junctions. FBL. 2009;14:2130–48.

    CAS  PubMed  Google Scholar 

  46. Kikuchi K, Poss KD. Cardiac regenerative capacity and mechanisms. Annu Rev Cell Dev Biol. 2012;28:719–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Garbern JC, Lee RT. Heart regeneration: 20 years of progress and renewed optimism. Dev Cell. 2022;57:424–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gong R, Jiang Z, Zagidullin N, Liu T, Cai B. Regulation of cardiomyocyte fate plasticity: a key strategy for cardiac regeneration. Signal Transduct Target Ther. 2021;6:31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Abu Rmilah A, et al. Understanding the marvels behind liver regeneration. Wiley Interdiscip Rev Dev Biol. 2019;8:e340.

    Article  PubMed  Google Scholar 

  50. Crowl JT, et al. Tissue-resident memory CD8+ T cells possess unique transcriptional, epigenetic and functional adaptations to different tissue environments. Nat Immunol. 2022;23:1121–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Masopust D, Soerens AG. Tissue-resident T cells and other resident leukocytes. Ann Rev Immunol. 2019;37:521–46.

    Article  CAS  Google Scholar 

  52. Hiebert PR, Wu D, Granville DJ. Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice. Cell Death Differ. 2013;20:1404–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hendel A, Granville DJ. Granzyme B cleavage of fibronectin disrupts endothelial cell adhesion, migration and capillary tube formation. Matrix Biol. 2013;32:14–22.

    Article  CAS  PubMed  Google Scholar 

  54. Shen Y, et al. Granzyme B deficiency protects against angiotensin II–induced cardiac fibrosis. Am J Pathol. 2016;186:87–100.

    Article  CAS  PubMed  Google Scholar 

  55. Bayer AL, et al. Cytotoxic T cells drive doxorubicin-induced cardiac fibrosis and systolic dysfunction. Nat Cardiovasc Res. 2024;3:970–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kaye J. CD160 and BTLA: LIGHTs out for CD4+ T cells. Nat Immunol. 2008;9:122–4.

    Article  CAS  PubMed  Google Scholar 

  57. Lai C, et al. CD8+CD103+ tissue-resident memory T cells convey reduced protective immunity in cutaneous squamous cell carcinoma. J Immunother Cancer. 2021;9:e001807.

  58. Tan CL, et al. CD160 stimulates CD8+ T-cell responses and is required for optimal protective immunity to Listeria monocytogenes. ImmunoHorizons. 2018;2:238–50.

    Article  CAS  PubMed  Google Scholar 

  59. Liu S, Zhang W, Liu K, Wang Y. CD160 expression on CD8+ T cells is associated with active effector responses but limited activation potential in pancreatic cancer. Cancer Immunol Immunother. 2020;69:789–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rodriguez-Barbosa JI, et al. HVEM, a cosignaling molecular switch, and its interactions with BTLA, CD160 and LIGHT. Cell Mol Immunol. 2019;16:679–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhao M, et al. Targeting fibrosis: mechanisms and clinical trials. Signal Transduct Target Ther. 2022;7:206.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Zhao X, Chen J, Sun H, Zhang Y, Zou D. New insights into fibrosis from the ECM degradation perspective: the macrophage-MMP-ECM interaction. Cell Biosci. 2022;12:117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liu B-q, et al. XAF1 prevents hyperproduction of type I interferon upon viral infection by targeting IRF7. EMBO Rep. 2023;24:e55387.

    Article  CAS  PubMed  Google Scholar 

  64. Trapnell C, et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol. 2014;32:381–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the Life Sciences Institute core facilities, Zhejiang University, for their technical assistance. This study was also supported by the National Key Research and Development Program of China (2025YFA1309100), the distinguished Young Scientist Fund of NSFC (82125016), and the National Natural Science Foundation of China Key Program (82230061). This research was supported by the National Natural Science Foundation of China, Special Program (82341216), and the Zhejiang Provincial Natural Science Foundation of China (LHDMD22H100002). This study was supported by the National Key Research and Development Program of China (2021YFA1101803 and 2021ZD0203304). This study was also supported by the Jiangsu Science and Technology Project (Social Development) (BE2019669) and the National Natural Science Foundation of China (82071046, 82100540). This study was also supported by the 111 Program (D20036).

Author information

Author notes

  1. These authors contributed equally: Kang Sun, Jia-xin Dong, Xin-tao Mao, Wen-ping Li.

Authors and Affiliations

  1. The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China

    Kang Sun, Jia-xin Dong, Yu Wang, Dan-dan Liu, Bing Yang, Jiang-yan Zhong & Jin Jin

  2. Center for Neuroimmunology and Health Longevity, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Xin-tao Mao, Wen-ping Li & Jin Jin

  3. Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China

    Xiao-mei Teng & Zhenya Shen

  4. School of Medical Engineering, Beijing Institute of Technology, Zhuhai, Guangdong Province, China

    Yi-yuan Li

  5. Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China

    Jin Jin

Authors
  1. Kang Sun
    View author publications

    Search author on:PubMed Google Scholar

  2. Jia-xin Dong
    View author publications

    Search author on:PubMed Google Scholar

  3. Xin-tao Mao
    View author publications

    Search author on:PubMed Google Scholar

  4. Wen-ping Li
    View author publications

    Search author on:PubMed Google Scholar

  5. Yu Wang
    View author publications

    Search author on:PubMed Google Scholar

  6. Xiao-mei Teng
    View author publications

    Search author on:PubMed Google Scholar

  7. Dan-dan Liu
    View author publications

    Search author on:PubMed Google Scholar

  8. Bing Yang
    View author publications

    Search author on:PubMed Google Scholar

  9. Jiang-yan Zhong
    View author publications

    Search author on:PubMed Google Scholar

  10. Zhenya Shen
    View author publications

    Search author on:PubMed Google Scholar

  11. Yi-yuan Li
    View author publications

    Search author on:PubMed Google Scholar

  12. Jin Jin
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Conceptualization, JJ and Y-yL; methodology, KS, J-xD, J-hX, YW, X-mT, D-dL, J-yZ, M-lT, and W-pL; investigation, KS, J-xD, YW, J-hX, X-mT, D-dL, J-yZ and M-lT; investigation, KS, J-xD, YW, X-mT, D-dL, J-yZ and M-lT; writing-original draft, JJ, Y-yL, KS and J-xD; writing-review & editing, JJ, and Y-yL; visualization, JJ, and Y-yL; supervision, JJ, and Y-yL; funding acquisition, JJ, and Y-yL.

Corresponding authors

Correspondence to Zhenya Shen, Yi-yuan Li or Jin Jin.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, K., Dong, Jx., Mao, Xt. et al. CD160+ intraepithelial lymphocytes and CCRL2+ macrophages drive differential repair in cardiac and liver injuries. Cell Mol Immunol 23, 186–203 (2026). https://doi.org/10.1038/s41423-025-01376-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41423-025-01376-6

Keywords

Search

Advanced search

Quick links