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The roles of tertiary lymphoid structures in chronic diseases

Nature Reviews Nephrology volume 19, pages 525–537 (2023)Cite this article

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Abstract

Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues that drive antigen-specific immune responses at sites of chronic inflammation. Unlike secondary lymphoid organs such as lymph nodes, TLSs lack capsules and have their own unique characteristics and functions. The presumed influence of TLSs on the disease course has led to widespread interest in obtaining a better understanding of their biology and function. Studies using single-cell analyses have suggested heterogeneity in TLS composition and phenotype, and consequently, functional correlates with disease progression are sometimes conflicting. The presence of TLSs correlates with a favourable disease course in cancer and infection. Conversely, in autoimmune diseases and chronic age-related inflammatory diseases including chronic kidney disease, the presence of TLSs is associated with a more severe disease course. However, the detailed mechanisms that underlie these clinical associations are not fully understood. To what extent the mechanisms of TLS development and maturation are shared across organs and diseases is also still obscure. Improved understanding of TLS development and function at the cellular and molecular levels may enable the exploitation of these structures to improve therapies for chronic diseases, including chronic kidney disease.

Key points

  • Tertiary lymphoid structures (TLSs) are organized lymphoid aggregates that develop in perivascular areas in response to disturbed tissue homeostasis.

  • TLSs serve as local immune niches to promote adaptive immunity; their unencapsulated structure enables direct exposure to diverse stimuli from an inflamed environment.

  • The development of TLSs in different organs involves common mechanisms that are presumably regulated by tissue-specific cues.

  • The presence of TLSs correlates with a favourable disease course in many types of cancer and infection.

  • In autoimmunity, chronic inflammation and ageing, the presence of TLSs correlates with pathological conditions and a more severe disease course.

  • Functional characterization of TLSs in human diseases and the development of interventions to induce or reduce TLSs could lead to promising therapeutic avenues.

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Fig. 1: Structural differences between secondary lymphoid organs and tertiary lymphoid structures.
Fig. 2: Maturation of tertiary lymphoid structures.
Fig. 3: Presence of tertiary lymphoid structures in different tumour types.

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Authors and Affiliations

  1. Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Yuki Sato & Motoko Yanagita

  2. Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland

    Karina Silina

  3. Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

    Maries van den Broek

  4. Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan

    Kiyoshi Hirahara

  5. Synergy Institute for Futuristic Mucosal Vaccine Research and Development, Chiba University, Chiba, Japan

    Kiyoshi Hirahara

  6. Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan

    Motoko Yanagita

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Y.S. and K.S. researched the data for the article. All authors contributed substantially to discussion of the content, and wrote the article. M.Y. reviewed and/or edited the manuscript before submission.

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Correspondence to Motoko Yanagita.

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M.Y. has received research grants from Mitsubishi Tanabe Pharma and Boehringer Ingelheim. The other authors declare no competing interests.

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Sato, Y., Silina, K., van den Broek, M. et al. The roles of tertiary lymphoid structures in chronic diseases. Nat Rev Nephrol 19, 525–537 (2023). https://doi.org/10.1038/s41581-023-00706-z

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