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Regulatory T cells in autoimmune kidney diseases and transplantation

Nature Reviews Nephrology volume 19, pages 544–557 (2023)Cite this article

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An Author Correction to this article was published on 04 September 2023

This article has been updated

Abstract

Regulatory T (Treg) cells that express the transcription factor forkhead box protein P3 (FOXP3) are naturally present in the immune system and have roles in the maintenance of immunological self-tolerance and immune system and tissue homeostasis. Treg cells suppress T cell activation, expansion and effector functions by various mechanisms, particularly by controlling the functions of antigen-presenting cells. They can also contribute to tissue repair by suppressing inflammation and facilitating tissue regeneration, for example, via the production of growth factors and the promotion of stem cell differentiation and proliferation. Monogenic anomalies of Treg cells and genetic variations of Treg cell functional molecules can cause or predispose patients to the development of autoimmune diseases and other inflammatory disorders, including kidney diseases. Treg cells can potentially be utilized or targeted to treat immunological diseases and establish transplantation tolerance, for example, by expanding natural Treg cells in vivo using IL-2 or small molecules or by expanding them in vitro for adoptive Treg cell therapy. Efforts are also being made to convert antigen-specific conventional T cells into Treg cells and to generate chimeric antigen receptor Treg cells from natural Treg cells for adoptive Treg cell therapies with the aim of achieving antigen-specific immune suppression and tolerance in the clinic.

Key points

  • Naturally occurring regulatory T (Treg) cells have roles in the maintenance of immunological self-tolerance and homeostasis.

  • Treg cells utilize a variety of cell contact-dependent and humoral factor-mediated mechanisms to exert their immunosuppressive functions, particularly by controlling the function of antigen-presenting cells.

  • Treg cell anomalies, for example, owing to mutations in genes that are associated with Treg cell functions, can cause autoimmune and inflammatory diseases, including autoimmune kidney diseases.

  • Treg cells can establish transplantation tolerance by suppressing the functions of immune cells that contribute to cell-mediated and/or antibody-mediated graft rejection.

  • In vivo expansion of natural Treg cells via administration of IL-2 or small molecules could be beneficial for the treatment of autoimmune diseases.

  • Adoptive Treg cell therapies using in vitro expanded natural or induced Treg cells or chimeric antigen receptor Treg cells are promising approaches to the treatment of autoimmune disease and induction of graft tolerance.

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Fig. 1: FOXP3+ Treg cells.
Fig. 2: Treg cell-mediated immune suppression and induction of long-term tolerance.
Fig. 3: Subpopulations of human FOXP3+ T cells.
Fig. 4: Potential approaches to establishing Treg cell-mediated dominant tolerance in autoimmune disease or transplantation.

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Acknowledgements

The authors thank the Ministry of Education, Culture, Sports, Science, Technology of Japan, and Japan Agency for Medical Research and Development for support of their research.

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Authors and Affiliations

  1. Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan

    Norihisa Mikami & Shimon Sakaguchi

  2. Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan

    Shimon Sakaguchi

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The authors contributed equally to all aspects of the article.

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Correspondence to Shimon Sakaguchi.

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S.S. is a founder and scientific advisor of RegCell, which aims to develop a novel Treg cell-based therapy for autoimmune disease. S.S. and N.M. are holders of a patent for use of a CDK8/19 inhibitor in Treg cell production.

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Nature Reviews Nephrology thanks Joanna Hester; Benoît Salomon; Megan Sykes, who co-reviewed with Kevin Breen; and Piotr Trzonkowski for their contribution to the peer review of this work.

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Glossary

Expression quantitative trait loci

Genetic variants that affect the expression of specific genes. An expression quantitative trait locus is a genomic locus that is associated with variation in gene expression levels across individuals or populations.

Genome organizer

A protein or protein complex that specifies the 3D architecture of the genome and is functionally important for gene regulation and control of gene expression programmes.

Latent TGFβ1

An inactive precursor form of the TGFβ protein that is produced by various cell types, including fibroblasts, macrophages, platelets and T cells. Latent TGFβ consists of the TGFβ protein bound to a latency-associated peptide (LAP) and a latent TGFβ-binding protein (LTBP).

Mediator complex

A multi-protein complex that acts as a bridge between gene-specific transcription factors and RNA polymerase. The mediator complex helps to coordinate and regulate the transcription process by facilitating the formation of a functional transcriptional pre-initiation complex at the promoter region of genes.

Operational tolerance

A state in which a transplant recipient with normal allograft function no longer requires immunosuppressive drugs to prevent rejection of the transplanted organ.

Pioneer factors

Transcription factors that can interact with nucleosomal DNA in silent or heterochromatin regions and make these regions accessible for other transcription factors to initiate gene activation.

Trogocytosis

A process by which immune cells exchange membrane fragments and/or proteins with other cells through direct cell-to-cell contact. This process can alter the function and/or identity of both cells.

Type 1 inflammation

A type of immune response that is characterized by the activation of TH1 cells, which secrete IFNγ and other pro-inflammatory cytokines, as well as macrophages and natural killer cells.

Type 2 inflammation

A type of immune response that is characterized by the activation of TH2 cells, eosinophils and mast cells, and by their secretion of cytokines such as IL-4, IL-5 and IL-13.

Type 3 inflammation

A type of immune response that is characterized by the activation of TH17 cells and their secretion of pro-inflammatory cytokines such as IL-17, IL-22 and IL-23.

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Mikami, N., Sakaguchi, S. Regulatory T cells in autoimmune kidney diseases and transplantation. Nat Rev Nephrol 19, 544–557 (2023). https://doi.org/10.1038/s41581-023-00733-w

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