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New insights into follicular helper T cell response and regulation in autoimmune pathogenesis

Cellular & Molecular Immunology volume 18, pages 1610–1612 (2021)Cite this article

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Follicular helper T (Tfh) cells play a key role in driving B cell activation and differentiation during germinal center reactions in immune responses and autoimmune development, and these cells are characterized by high expression of CXCR5, PD1, ICOS, IL-21 and BCL6. Increasing evidence indicates that the functional dysregulation of Tfh cells contributes to the pathogenesis of autoimmune diseases, including primary Sjögren’s syndrome (pSS), which is a common autoimmune disease characterized by lymphocytic infiltration and tissue inflammation in salivary glands (SGs) and lacrimal glands that leads to dry mouth and dry eyes.1 Here, we provide a brief commentary on recent advances in understanding the Tfh cell response with a focus on new insights into Tfh cell regulation and therapeutic implications in autoimmune diseases.

Clinical investigations have shown that increased frequencies of Tfh-like cells in peripheral blood are positively correlated with disease activities in both pSS and systemic lupus erythematosus (SLE) patients.1,2 The ratios of T follicular regulatory (Tfr) cells and Tfh cells in peripheral blood indicates the formation of ectopic lymphoid structures (ELSs) and lymphocytic infiltration in SGs, suggesting that the blood Tfr/Tfh ratio may serve as a biomarker of disease severity in pSS patients.3 Recently, functionally distinct Tfh cell subsets that share features of Th1, Th2, and Th17 cells have been identified by the differential expression of CCR6 and CXCR3.1 The frequencies of CD4+CXCR5+CCR6+ Th17-like Tfh cells with high expression levels of IL-21 and Bcl-6 are increased in pSS patients and are positively correlated with the levels of immunoglobulin and anti-Ro/SSA and EULAR Sjögren’s syndrome Disease Activity Index (ESSDAI) scores.4 A circulating CCR7loPD-1hi subset of Tfh cells is associated with disease activity scores and SG inflammation in pSS patients.5 It has been shown that Tfh cells and pathogenic T peripheral helper (Tph) cells are expanded in the peripheral blood and SGs, accompanied by the formation of ectopic germinal centers in pSS patients.6 Moreover, Tfh cells selectively infiltrate SG tissues, accompanied by the formation of ELSs, and are aberrantly expanded in parotid mucosa-associated lymphoid tissue (MALT) lymphoma.6 Thus, these clinical observations suggest that Tfh cells and functional subsets may serve as biomarkers for diagnosis and disease activity assessment in pSS patients. Studies of pSS animal models have demonstrated the critical involvement of Tfh cells during pSS pathogenesis. The numbers of splenic Tfh cells are positively correlated with the severity of autoimmune lesions in NFS/sld mice with neonatal thymectomy, which is a murine model of pSS.7 During the induction of experimental Sjögren’s syndrome (ESS), CD4Cre Bcl6fl/fl mice that lack Tfh cells show almost no lymphocytic infiltration, while wild-type (WT) mice display profound glandular inflammation in the SGs.8 Moreover, CD4Cre Bcl6fl/fl mice exhibit attenuated germinal center B cell responses, reduced serum autoantibody levels, and decreased SG IgG deposition compared with those of their WT counterparts, suggesting a pathogenic role of Tfh cells during ESS development.8

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 82071817 and 82004171), the Chongqing International Institute for Immunology (2020YJC10), the Hong Kong Research Grants Council (17149716), Fundamental Research Funds for Central Public Welfare Research Institutes (ZZ13-YQ-033-C1), the Young Elite Scientist Sponsorship Program of CACM (CACM-2020-QNRC2-05) and HKU Seed Funding for Strategic Interdisciplinary Research Scheme.

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  1. These authors contributed equally: Fan Xiao, Man Han

Authors and Affiliations

  1. Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong; Chongqing International Institute for Immunology, Hong Kong, China

    Fan Xiao & Liwei Lu

  2. Division of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China

    Man Han & Quan Jiang

  3. Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University and Jiangsu Key Laboratory of Laboratory Medicine, Zhenjiang, China

    Ke Rui & Jie Tian

  4. Department of Rheumatology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Xiangyan Ai & Futao Zhao

  5. Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China

    Wen Zhang & Yan Zhao

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Correspondence to Quan Jiang or Liwei Lu.

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Xiao, F., Han, M., Rui, K. et al. New insights into follicular helper T cell response and regulation in autoimmune pathogenesis. Cell Mol Immunol 18, 1610–1612 (2021). https://doi.org/10.1038/s41423-021-00688-7

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