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T follicular helper cells and T follicular regulatory cells in rheumatic diseases


As a hallmark of autoimmune rheumatic diseases, autoantibodies have been used in diagnosis for decades. However, the immunological mechanism underlying their generation has only become clear following the identification of T follicular helper (TFH) cells and T follicular regulatory (TFR) cells. TFH cells are instrumental in supporting antibody affinity maturation in germinal centre reactions and humoral memory formation, whereas TFR cells suppress TFH cell-mediated antibody responses. Evidence indicates that patients with autoimmune rheumatic diseases have increased numbers of TFH cells that can be hyperactive, and also potentially have altered numbers of TFR cells with reduced function, suggesting a conceivable dysregulation in the balance between TFH cells and TFR cells in these diseases. Therefore, by identifying the molecular mechanisms underlying the development and function of these cell populations, new opportunities have emerged to develop novel therapeutic targets. An increased knowledge of TFH cells and TFR cells has inspired, and hopefully will inspire more, approaches to reinstate the balance of these cells in the prevention and treatment of rheumatic diseases.

Key points

  • T follicular helper (TFH) cells promote autoantibody production and are present at increased amounts in mouse models of autoimmune diseases and in patients with autoimmune rheumatic diseases.

  • T follicular regulatory (TFR) cells have different T cell receptor repertoires than TFH cells and suppress the production of autoantibodies.

  • TFH cells and TFR cells in secondary lymphoid organs and their related populations in the circulation or non-lymphoid tissues have different characteristic phenotypes.

  • Immunotherapies targeting co-stimulatory molecules or cytokine signalling pathways tilt the balance of TFH cells and TFR cells towards inhibiting autoantibody production in rheumatic diseases.

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The authors thank members of the Yu and Graca groups for intellectual input and E. Bartlett for editing. The work of the authors was funded by grants from the National Key Research and Development Program of China (2017YFC0909003 to D.Y.), the National Natural Science Foundation of China (31600708 to J.D. and 81429003 to D.Y.), the Australian National Health and Medical Research Council (GNT1147769 to D.Y.), the Shandong Provincial Natural Science Foundation, China (ZR2016YL013 to D.Y. and ZR2015YL005 to D.Y. and Y.W.) and the Priority Research Program of the Shandong Academy of Sciences (to D.Y. and Y.W.). D.Y. is supported by the Bellberry-Viertel Senior Medical Research Fellowship, Innovative Research Team of High-Level Local Universities in Shanghai, and the Taishan Scholars Program of Shandong Province, China.

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Nature Reviews Rheumatology thanks H. Ueno, Y. Tanaka and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Review criteria

A search for original articles published between 2000 and 2019 and focusing on 2009 onwards was performed in MEDLINE and PubMed. The search terms used were “TFH”, “TFR”, “autoimmunity” and “rheumatic disease”, alone and in combination. All articles identified were English-language, full-text papers. We also searched the reference lists of identified articles for further relevant papers.

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D.Y. and L.G. researched data for this article. J.D., Y.W., V.F., L.G. and D.Y. provided substantial contributions to discussions of content and wrote the article. All authors reviewed and/or edited the article before submission. J.D. and Y.W. contributed equally to this article.

Correspondence to Luis Graca or Di Yu.

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Ectopic lymphoid structure

Ectopic lymphoid structures are lymphoid aggregates that range from clusters of B cells and T cells to highly organized structures that resemble functional germinal centres, and often develop in inflamed tissues.

Peyer’s patches

Peyer’s patches are organized lymphoid follicles located primarily in the submucosa layer of the ileum that have important immune sensing functions for the intestines.

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Fig. 1: Phenotypes of TFH cell and TFR cell subsets.
Fig. 2: Function of TFH cells and TFR cells in germinal centres.
Fig. 3: Targeting TFH cells and TFR cells in autoimmune rheumatic diseases.