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  • Perspective
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Structural immunity: immune cells as architects of tissue barriers

Nature Reviews Immunology (2025)Cite this article

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Abstract

The concept of structural immunity, as defined in this Perspective, posits that the first line of immune defence against foreign agents and tissue damage involves the preventative, physical reinforcement of tissue barriers and that this fundamental task can be directly or indirectly regulated by immune cells. Indeed, several types of leukocytes can help build protective barriers when required, potentially either by depositing matrix components themselves in certain circumstances or, more generally, by interactions with canonical structural cells and the existing extracellular matrix. This concept of structural functions of immune cells challenges the rigidity with which mammalian tissue organization and immune defence have been traditionally compartmentalized. Although there is strong momentum in the evidence for structural immunity that has been acquired so far, the field lacks a comprehensive overview of these data as well as a critical evaluation of this concept. Here, we place independent findings from several groups into a working model of immune cells as the architects of tissue barriers, to present a framework on which new concepts and findings in this area can develop.

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Fig. 1: Models of structural immunity.
Fig. 2: Division of labour between structural cells and immune cells.

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Acknowledgements

The authors thank members of their laboratories for past and present discussions and inspiration to write this article. Work for this article was supported by grants R01AI165661 from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) and the Transatlantic Network of Excellence (TNE-18CVD04) from the Leducq Foundation. A.O. was supported by the Swiss National Science Foundation (P500PB-206852). T.V. received support from La Caixa Foundation (ID 100010434) with fellowship code LCF/BQ/DR21/11880022, and from Boehringer Ingelheim Fonds.

Author information

Author notes

  1. These authors contributed equally: Alaz Ozcan, Tommaso Vicanolo.

Authors and Affiliations

  1. Department of Immunobiology, Program of Vascular Biology and Therapeutics, Yale University, New Haven, CT, USA

    Alaz Ozcan & Andrés Hidalgo

  2. Center for Human Immunology, University of Zurich, Zurich, Switzerland

    Alaz Ozcan

  3. Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland

    Alaz Ozcan

  4. Program of Cardiovascular Regeneration, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

    Tommaso Vicanolo & Andrés Hidalgo

  5. Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore

    Veronique Angeli

  6. Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore

    Veronique Angeli

  7. Université Côte d’Azur, INSERM, C3M, Nice, France

    Veronique Angeli

  8. Chinese Institutes for Medical Research, Institute of Regenerative Biology and Medicine, Beijing, China

    Yuval Rinkevich

  9. School of Basic Medical Sciences, Capital Medical University, Beijing, China

    Yuval Rinkevich

Authors
  1. Alaz Ozcan
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  2. Tommaso Vicanolo
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  3. Veronique Angeli
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  4. Yuval Rinkevich
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  5. Andrés Hidalgo
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Contributions

A.O., T.V. and A.H. researched data for and wrote the article. All authors contributed substantially to discussion of the content and reviewed the manuscript before submission.

Corresponding authors

Correspondence to Alaz Ozcan or Andrés Hidalgo.

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Nature Reviews Immunology thanks Kory Lavine and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Ozcan, A., Vicanolo, T., Angeli, V. et al. Structural immunity: immune cells as architects of tissue barriers. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01230-w

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