Advertisement

Imbalance of circulating Tfr/Tfh ratio in patients with rheumatoid arthritis

  • Xiuzhen Wang
  • Chunshu Yang
  • Feng Xu
  • Lin Qi
  • Jianing Wang
  • Pingting Yang
Original Article

Abstract

Follicular helper T(Tfh) cells and follicular regulatory T(Tfr) cells are critical for the development and maintenance of germinal center and humoral immune responses. Accumulating evidence has demonstrated that the dysregulation of either Tfh or Tfr cells contributes to the pathogenesis of autoimmune diseases. The aim of this study was to examine the numbers of Tfh and Tfr cells in patients with rheumatoid arthritis (RA). Twenty-four patients with RA patients and 20 health controls (HCs) were enrolled in this study. We analyzed the numbers of Tfh (CD4+ CXCR5+ PD-1hi) cells and Tfr (CD4+ CXCR5+CD127lo) cells in 24 RA patients via flow cytometry. The level of the soluble PD-1 and its ligands (sPD-L1 and sPDL-2) were examined by ELISA. Flow cytometry revealed that both circulating Tfh and Tfr cells were increased in RA patients compared with HCs. More importantly, the ratio of Tfr/Tfh was decreased, indicating a disruption of the balance between Tfh and Tfr. The Tfr/Tfh ratio was inversely correlated with level of serum CRP, ESR, RF, anti-CCP, IgG and DAS28 index. We also found that the serum level of sPD-1 was significantly elevated in the RA patients, which was positively correlated with CRP, ESR and the number of Tfh cells. These results indicate that an imbalance of circulating Tfr and Tfh cells may be involved in the immunopathogenesis of RA and may provide novel insight for the development of RA therapies.

Keywords

Rheumatoid arthritis Follicular helper T cell(Tfh) Follicular regulatory T cell(Tfr) Tfr/Tfh PD-1 

Abbreviations

RA

Rheumatoid arthritis

cTfh

Circulating follicular helper T

cTfr

Circulating follicular regulatory T

GC

Germinal center

ELISA

Enzyme‐linked immunosorbent assay

CRP

C-reaction protein

ESR

Erythrocyte sedimentation rate

IgG

Immunoglobulin G

RF

Rheumatoid factor

CXCR5

CXC chemokine receptor 5

CCP

Cyclic citrullinated peptide

sPD-1

Soluble PD-1

sPD-L1

Soluble PD-L1

sPD-L2

Soluble PD-L2

DAS28

Disease activity score in 28 joints

DMARDs

Disease-modifying antirheumatic drug

Notes

Acknowledgements

This work was supported by the following grants: foundation from clinical medical research center of Shenyang City (18_009-4-03 to PT.Y.), foundation from the Major State Research Development Program of Liaoning, China (No. 2017225024 to PT.Y.), foundation from the Project for Construction of Major Discipline Platform in Universities of Liaoning province, China (2017001 to PT.Y.), the Program of the Distinguished Professor of Liaoning Province, Rheumatology (2017 to PT.Y.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The studies have been approved by the ethics committee of the first affiliated hospital of China Medical University. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Firestein GS. Immunologic mechanisms in the pathogenesis of rheumatoid arthritis. J Clin Rheumatol. 2005;11(3 Suppl):S39–44.CrossRefGoogle Scholar
  2. 2.
    Jutley G, Raza K, Buckley CD. New pathogenic insights into rheumatoid arthritis. Curr Opin Rheumatol. 2015;27(3):249–55.  https://doi.org/10.1097/BOR.0000000000000174.CrossRefPubMedGoogle Scholar
  3. 3.
    Angelotti F, Parma A, Cafaro G, Capecchi R, Alunno A, Puxeddu I. One year in review 2017: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 2017;35(3):368–78.PubMedGoogle Scholar
  4. 4.
    Craft JE. Follicular helper T cells in immunity and systemic autoimmunity. Nat Rev Rheumatol. 2012;8(6):337–47.  https://doi.org/10.1038/nrrheum.2012.58.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 2011;29:621–63.  https://doi.org/10.1146/annurev-immunol-031210-101400.CrossRefPubMedGoogle Scholar
  6. 6.
    Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011;17(8):983–8.  https://doi.org/10.1038/nm.2426.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Park HJ, Kim DH, Lim SH, Kim WJ, Youn J, Choi YS, et al. Insights into the role of follicular helper T cells in autoimmunity. Immune Netw. 2014;14(1):21–9.  https://doi.org/10.4110/in.2014.14.1.21.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Vanderleyden I, Linterman MA, Smith KG. Regulatory T cells and control of the germinal centre response. Arthritis Res therapy. 2014;16(5):471.CrossRefGoogle Scholar
  9. 9.
    Zhu Y, Zou L, Liu YC. T follicular helper cells, T follicular regulatory cells and autoimmunity. Int Immunol. 2016;28(4):173–9.  https://doi.org/10.1093/intimm/dxv079.CrossRefPubMedGoogle Scholar
  10. 10.
    Sage PT, Sharpe AH. T follicular regulatory cells. Immunol Rev. 2016;271(1):246–59.  https://doi.org/10.1111/imr.12411.CrossRefPubMedGoogle Scholar
  11. 11.
    Vinuesa CG, Cook MC. Blood relatives of follicular helper T cells. Immunity. 2011;34(1):10–2.  https://doi.org/10.1016/j.immuni.2011.01.006.CrossRefPubMedGoogle Scholar
  12. 12.
    He J, Tsai LM, Leong YA, Hu X, Ma CS, Chevalier N, et al. Circulating precursor CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity. 2013;39(4):770–81.  https://doi.org/10.1016/j.immuni.2013.09.007.CrossRefPubMedGoogle Scholar
  13. 13.
    Wei Y, Feng J, Hou Z, Wang XM, Yu D. Flow cytometric analysis of circulating follicular helper T (Tfh) and follicular regulatory T (Tfr) populations in human blood. Methods Mol Biol. 2015;1291:199–207.  https://doi.org/10.1007/978-1-4939-2498-1_17.CrossRefPubMedGoogle Scholar
  14. 14.
    Sage PT, Alvarez D, Godec J, von Andrian UH, Sharpe AH. Circulating T follicular regulatory and helper cells have memory-like properties. J Clin Invest. 2014;124(12):5191–204.  https://doi.org/10.1172/JCI76861.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Xu B, Wang S, Zhou M, Huang Y, Fu R, Guo C, et al. The ratio of circulating follicular T helper cell to follicular T regulatory cell is correlated with disease activity in systemic lupus erythematosus. Clin Immunol. 2017;183:46–53.  https://doi.org/10.1016/j.clim.2017.07.004.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wen Y, Yang B, Lu J, Zhang J, Yang H, Li J. Imbalance of circulating CD4(+)CXCR5(+)FOXP3(+) Tfr-like cells and CD4(+)CXCR5(+)FOXP3(−) Tfh-like cells in myasthenia gravis. Neurosci Lett. 2016;630:176–82.  https://doi.org/10.1016/j.neulet.2016.07.049.CrossRefPubMedGoogle Scholar
  17. 17.
    Wang X, Zhu Y, Zhang M, Hou J, Wang H, Jiang Y, et al. The shifted balance between circulating follicular regulatory T cells and follicular helper T cells in patients with ulcerative colitis. Clin Sci (Lond). 2017;131(24):2933–45.  https://doi.org/10.1042/CS20171258.CrossRefGoogle Scholar
  18. 18.
    Zheng J, Wang T, Zhang L, Cui L. Dysregulation of Circulating Tfr/Tfh Ratio in primary biliary cholangitis. Scand J Immunol. 2017;86(6):452–61.  https://doi.org/10.1111/sji.12616.CrossRefPubMedGoogle Scholar
  19. 19.
    Arroyo-Villa I, Bautista-Caro MB, Balsa A, Aguado-Acin P, Bonilla-Hernan MG, Plasencia C, et al. Constitutively altered frequencies of circulating follicullar helper T cell counterparts and their subsets in rheumatoid arthritis. Arthritis Res Therapy. 2014;16(6):500.  https://doi.org/10.1186/s13075-014-0500-6.CrossRefGoogle Scholar
  20. 20.
    Wang J, Shan Y, Jiang Z, Feng J, Li C, Ma L, et al. High frequencies of activated B cells and T follicular helper cells are correlated with disease activity in patients with new-onset rheumatoid arthritis. Clin Exp Immunol. 2013;174(2):212–20.  https://doi.org/10.1111/cei.12162.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ma J, Zhu C, Ma B, Tian J, Baidoo SE, Mao C, et al. Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis. Clin Dev Immunol. 2012;2012:827480.  https://doi.org/10.1155/2012/827480.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Chakera A, Bennett SC, Morteau O, Bowness P, Luqmani RA, Cornall RJ. The phenotype of circulating follicular-helper T cells in patients with rheumatoid arthritis defines CD200 as a potential therapeutic target. Clin Dev Immunol. 2012;2012:948218.  https://doi.org/10.1155/2012/948218.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Liu R, Wu Q, Su D, Che N, Chen H, Geng L, et al. A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis Res Therapy. 2012;14(6):R255.  https://doi.org/10.1186/ar4100.CrossRefGoogle Scholar
  24. 24.
    Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. Rheumatoid arthritis classification criteria: an American College of Rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81.  https://doi.org/10.1002/art.27584.CrossRefPubMedGoogle Scholar
  25. 25.
    Prevoo ML, van ‘t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van de Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38(1):44–8.CrossRefGoogle Scholar
  26. 26.
    Simpson N, Gatenby PA, Wilson A, Malik S, Fulcher DA, Tangye SG, et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum. 2010;62(1):234–44.  https://doi.org/10.1002/art.25032.CrossRefPubMedGoogle Scholar
  27. 27.
    Good-Jacobson KL, Szumilas CG, Chen L, Sharpe AH, Tomayko MM, Shlomchik MJ. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol. 2010;11(6):535–42.  https://doi.org/10.1038/ni.1877.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zhu C, Ma J, Liu Y, Tong J, Tian J, Chen J, et al. Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J Clin Endocrinol Metab. 2012;97(3):943–50.  https://doi.org/10.1210/jc.2011-2003.CrossRefPubMedGoogle Scholar
  29. 29.
    Ma L, Zhao P, Jiang Z, Shan Y, Jiang Y. Imbalance of different types of CD4(+) forkhead box protein 3 (FoxP3)(+) T cells in patients with new-onset systemic lupus erythematosus. Clin Exp Immunol. 2013;174(3):345–55.  https://doi.org/10.1111/cei.12189.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sage PT, Francisco LM, Carman CV, Sharpe AH. The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat Immunol. 2013;14(2):152–61.  https://doi.org/10.1038/ni.2496.CrossRefPubMedGoogle Scholar
  31. 31.
    Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203(7):1701–11.  https://doi.org/10.1084/jem.20060772.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med. 2011;17(8):975–82.  https://doi.org/10.1038/nm.2425.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203(7):1693–700.  https://doi.org/10.1084/jem.20060468.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Hartigan-O’Connor DJ, Poon C, Sinclair E, McCune JM. Human CD4+ regulatory T cells express lower levels of the IL-7 receptor alpha chain (CD127), allowing consistent identification and sorting of live cells. J Immunol Methods. 2007;319(1–2):41–52.  https://doi.org/10.1016/j.jim.2006.10.008.CrossRefPubMedGoogle Scholar
  35. 35.
    Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011;34(1):108–21.  https://doi.org/10.1016/j.immuni.2010.12.012.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Rheumatology and ImmunologyFirst Affiliated Hospital, China Medical UniversityShenyangPeople’s Republic of China
  2. 2.Department of Rheumatology and ImmunologyFirst Affiliated Hospital, Jinzhou Medical UniversityJinzhouPeople’s Republic of China
  3. 3.Department of First Cancer InstituteFirst Affiliated Hospital, China Medical UniversityShenyangPeople’s Republic of China

Personalised recommendations