Skip to main content

Advertisement

SpringerLink
Log in

Follicular helper T cells: potential therapeutic targets in rheumatoid arthritis

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease with joint and systemic inflammation that is accompanied by the production of autoantibodies, such as rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Follicular helper T (Tfh) cells, which are a subset of CD4+ T cells, facilitate germinal center (GC) reactions by providing signals required for high-affinity antibody production and the generation of long-lived antibody-secreting plasma cells. Uncontrolled expansion of Tfh cells is observed in various systemic autoimmune diseases. Particularly, the frequencies of circulating Tfh-like (cTfh-like) cells, their subtypes and synovial-infiltrated T helper cells correlate with disease activity in RA patients. Therefore, reducing autoantibody production and restricting excessive Tfh cell responses are ideal ways to control RA pathogenesis. The present review summarizes current knowledge of the involvement of Tfh cells in RA pathogenesis and highlights the potential of these cells as therapeutic targets.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Weyand CM, Goronzy JJ (2021) The immunology of rheumatoid arthritis. Nat Immunol 22(1):10–18. https://doi.org/10.1038/s41590-020-00816-x

    Article  CAS  PubMed  Google Scholar 

  2. Schett G, Tanaka Y, Isaacs JD (2020) Why remission is not enough: underlying disease mechanisms in RA that prevent cure. Nat Rev Rheumatol. https://doi.org/10.1038/s41584-020-00543-5

    Article  PubMed  PubMed Central  Google Scholar 

  3. Firestein GS, McInnes IB (2017) Immunopathogenesis of rheumatoid arthritis. Immunity 46(2):183–196. https://doi.org/10.1016/j.immuni.2017.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vinuesa CG, Linterman MA, Yu D, MacLennan IC (2016) Follicular helper T cells. Annu Rev Immunol 34:335–368. https://doi.org/10.1146/annurev-immunol-041015-055605

    Article  CAS  PubMed  Google Scholar 

  5. Deng J, Fan C, Gao X et al (2018) Signal transducer and activator of transcription 3 hyperactivation associates with follicular helper T cell differentiation and disease activity in rheumatoid arthritis. Front Immunol 9:1226. https://doi.org/10.3389/fimmu.2018.01226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kim CJ, Lee CG, Jung JY et al (2018) The transcription factor Ets1 suppresses T follicular helper type 2 cell differentiation to halt the onset of systemic lupus erythematosus. Immunity 49(6):1034–1048 e1038. https://doi.org/10.1016/j.immuni.2018.10.012

    Article  CAS  PubMed  Google Scholar 

  7. Pontarini E, Murray-Brown WJ, Croia C et al (2020) Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjögren’s syndrome with ectopic germinal centres and MALT lymphoma. Ann Rheum Dis 79(12):1588–1599. https://doi.org/10.1136/annrheumdis-2020-217646

    Article  CAS  PubMed  Google Scholar 

  8. Yang J, Geng L, Ma Y et al (2021) SLAMs negatively regulate IL-21 production in Tfh-like cells from allergic rhinitis patients. J Asthma Allergy 14:361–369. https://doi.org/10.2147/JAA.S291879

  9. Chen Y, Lin W, Yang H et al (2018) Aberrant expansion and function of follicular helper T cell subsets in IgG4-related disease. Arthritis Rheumatol 70(11):1853–1865. https://doi.org/10.1002/art.40556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Faliti CE, Gualtierotti R, Rottoli E et al (2019) P2X7 receptor restrains pathogenic Tfh cell generation in systemic lupus erythematosus. J Exp Med 216(2):317–336. https://doi.org/10.1084/jem.20171976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Penatti A, Facciotti F, De Matteis R et al (2017) Differences in serum and synovial CD4+ T cells and cytokine profiles to stratify patients with inflammatory osteoarthritis and rheumatoid arthritis. Arthritis Res Ther 19(1):103. https://doi.org/10.1186/s13075-017-1305-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Arroyo-Villa I, Bautista-Caro MB, Balsa A et al (2014) Constitutively altered frequencies of circulating follicullar helper T cell counterparts and their subsets in rheumatoid arthritis. Arthritis Res Ther 16(6):500. https://doi.org/10.1186/s13075-014-0500-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhou H, Hu B, Zhaopeng Z et al (2019) Elevated circulating T cell subsets and cytokines expression in patients with rheumatoid arthritis. Clin Rheumatol. https://doi.org/10.1007/s10067-019-04465-w

    Article  PubMed  Google Scholar 

  14. Ise W, Kurosaki T (2019) Plasma cell differentiation during the germinal center reaction. Immunol Rev 288(1):64–74. https://doi.org/10.1111/imr.12751

    Article  CAS  PubMed  Google Scholar 

  15. Cucak H, Yrlid U, Reizis B, Kalinke U, Johansson-Lindbom B (2009) Type I interferon signaling in dendritic cells stimulates the development of lymph-node-resident T follicular helper cells. Immunity 31(3):491–501. https://doi.org/10.1016/j.immuni.2009.07.005

    Article  CAS  PubMed  Google Scholar 

  16. Ma CS, Avery DT, Chan A et al (2012) Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood 119(17):3997–4008. https://doi.org/10.1182/blood-2011-11-392985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shi J, Hou S, Fang Q, Liu X, Liu X, Qi H (2018) PD-1 controls follicular T helper cell positioning and function. Immunity 49(2):264–274 e264. https://doi.org/10.1016/j.immuni.2018.06.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Crotty S (2019) T follicular helper cell biology: a decade of discovery and diseases. Immunity 50(5):1132–1148. https://doi.org/10.1016/j.immuni.2019.04.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang Y, Shi J, Yan J et al (2017) Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells. Nat Immunol 18(8):921–930. https://doi.org/10.1038/ni.3788

    Article  CAS  PubMed  Google Scholar 

  20. Kawamoto S, Tran TH, Maruya M et al (2012) The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science 336(6080):485–489. https://doi.org/10.1126/science.1217718

    Article  CAS  PubMed  Google Scholar 

  21. Good-Jacobson KL, Szumilas CG, Chen L, Sharpe AH, Tomayko MM, Shlomchik MJ (2010) PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol 11(6):535–542. https://doi.org/10.1038/ni.1877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Papa I, Saliba D, Ponzoni M et al (2017) TFH-derived dopamine accelerates productive synapses in germinal centres. Nature 547(7663):318–323. https://doi.org/10.1038/nature23013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Han S, Hathcock K, Zheng B, Kepler TB, Hodes R, Kelsoe G (1995) Cellular interaction in germinal centers. Roles of CD40 ligand and B7–2 in established germinal centers. J Immunol 155(2):556–567

    CAS  PubMed  Google Scholar 

  24. Kawabe T, Naka T, Yoshida K et al (1994) The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1(3):167–178

    Article  CAS  Google Scholar 

  25. Xu J, Foy TM, Laman JD et al (1994) Mice deficient for the CD40 ligand. Immunity 1(5):423–431

    Article  CAS  Google Scholar 

  26. Allen CD, Okada T, Tang HL, Cyster JG (2007) Imaging of germinal center selection events during affinity maturation. Science 315(5811):528–531. https://doi.org/10.1126/science.1136736

    Article  CAS  PubMed  Google Scholar 

  27. Koguchi Y, Buenafe AC, Thauland TJ et al (2012) Preformed CD40L is stored in Th1, Th2, Th17, and T follicular helper cells as well as CD4+ 8- thymocytes and invariant NKT cells but not in Treg cells. PLoS ONE 7(2):e31296. https://doi.org/10.1371/journal.pone.0031296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gardell JL, Parker DC (2017) CD40L is transferred to antigen-presenting B cells during delivery of T-cell help. Eur J Immunol 47(1):41–50. https://doi.org/10.1002/eji.201646504

    Article  CAS  PubMed  Google Scholar 

  29. Michel NA, Zirlik A, Wolf D (2017) CD40L and its receptors in atherothrombosis-an update. Front Cardiovasc Med 4:40. https://doi.org/10.3389/fcvm.2017.00040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ela S, Mager I, Breakefield XO, Wood MJ (2013) Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 12(5):347–357. https://doi.org/10.1038/nrd3978

    Article  CAS  Google Scholar 

  31. Sprague DL, Elzey BD, Crist SA, Waldschmidt TJ, Jensen RJ, Ratliff TL (2008) Platelet-mediated modulation of adaptive immunity: unique delivery of CD154 signal by platelet-derived membrane vesicles. Blood 111(10):5028–5036. https://doi.org/10.1182/blood-2007-06-097410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Skokos D, Le Panse S, Villa I et al (2001) Mast cell-dependent B and T lymphocyte activation is mediated by the secretion of immunologically active exosomes. J Immunol 166(2):868–876

    Article  CAS  Google Scholar 

  33. Perez-Hernandez D, Gutierrez-Vazquez C, Jorge I et al (2013) The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. J Biol Chem 288(17):11649–11661. https://doi.org/10.1074/jbc.M112.445304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Blanchard N, Lankar D, Faure F et al (2002) TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J Immunol 168(7):3235–3241

    Article  CAS  Google Scholar 

  35. Lu J, Wu J, Xie F et al (2019) CD4(+) T cell-released extracellular vesicles potentiate the efficacy of the HBsAg vaccine by enhancing B cell responses. Adv Sci (Weinh) 6(23):1802219. https://doi.org/10.1002/advs.201802219

    Article  CAS  Google Scholar 

  36. Fernandez-Messina L, Rodriguez-Galan A, de Yebenes VG et al (2020) Transfer of extracellular vesicle-microRNA controls germinal center reaction and antibody production. EMBO Rep https://doi.org/10.15252/embr.201948925

  37. Morita R, Schmitt N, Bentebibel SE et al (2011) Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34(1):108–121. https://doi.org/10.1016/j.immuni.2010.12.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Schmitt N, Bentebibel SE, Ueno H (2014) Phenotype and functions of memory Tfh cells in human blood. Trends Immunol 35(9):436–442. https://doi.org/10.1016/j.it.2014.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ricard L, Jachiet V, Malard F et al (2019) Circulating follicular helper T cells are increased in systemic sclerosis and promote plasmablast differentiation through the IL-21 pathway which can be inhibited by ruxolitinib. Ann Rheum Dis 78(4):539–550. https://doi.org/10.1136/annrheumdis-2018-214382

    Article  CAS  PubMed  Google Scholar 

  40. Choi JY, Ho JH, Pasoto SG et al (2015) Circulating follicular helper-like T cells in systemic lupus erythematosus: association with disease activity. Arthritis Rheumatol 67(4):988–999. https://doi.org/10.1002/art.39020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Taylor DK, Mittereder N, Kuta E et al (2018) T follicular helper-like cells contribute to skin fibrosis. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aaf5307

    Article  PubMed  Google Scholar 

  42. Ma J, Zhu C, Ma B et al (2012) Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis. Clin Dev Immunol 2012:827480. https://doi.org/10.1155/2012/827480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fortea-Gordo P, Nuño L, Villalba A et al (2019) Two populations of circulating PD-1hiCD4 T cells with distinct B cell helping capacity are elevated in early rheumatoid arthritis. Rheumatology (Oxford) 58(9):1662–1673. https://doi.org/10.1093/rheumatology/kez169

    Article  CAS  Google Scholar 

  44. Liu Y, Yuan X, Li X, Cui D, Xie J (2018) Constitutive changes in circulating follicular helper T cells and their subsets in patients with Graves’ disease. J Immunol Res 2018:8972572. https://doi.org/10.1155/2018/8972572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sun WK, Bai Y, Yi MM et al (2019) Expression of T follicular helper lymphocytes with different subsets and analysis of serum IL-6, IL-17, TGF-beta and MMP-3 contents in patients with rheumatoid arthritis. Eur Rev Med Pharmacol Sci 23(1):61–69

    PubMed  Google Scholar 

  46. Chen XM, Li J, Zhang XY et al (2016) Significance of different T follicular helper subsets in rheumatoid arthritis. Beijing Da Xue Xue Bao Yi Xue Ban 48(6):958–963

    CAS  PubMed  Google Scholar 

  47. Sun WK, Bai Y, Yi MM et al (2019) Expression of T follicular helper lymphocytes with different subsets and analysis of serum IL-6, IL-17, TGF-β and MMP-3 contents in patients with rheumatoid arthritis. Eur Rev Med Pharmacol Sci 23(1):61–69

    PubMed  Google Scholar 

  48. Takeshita M, Suzuki K, Kondo Y et al (2019) Multi-dimensional analysis identified rheumatoid arthritis-driving pathway in human T cell. Ann Rheum Dis 78(10):1346–1356. https://doi.org/10.1136/annrheumdis-2018-214885

    Article  CAS  PubMed  Google Scholar 

  49. Kurata I, Matsumoto I, Ohyama A et al (2019) Potential involvement of OX40 in the regulation of autoantibody sialylation in arthritis. Ann Rheum Dis 78(11):1488–1496. https://doi.org/10.1136/annrheumdis-2019-215195

    Article  CAS  PubMed  Google Scholar 

  50. Singh D, Henkel M, Sendon B et al (2016) Analysis of CXCR5(+)Th17 cells in relation to disease activity and TNF inhibitor therapy in Rheumatoid Arthritis. Sci Rep 6:39474. https://doi.org/10.1038/srep39474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Costantino AB, Acosta CDV, Onetti L, Mussano E, Cadile II, Ferrero PV (2017) Follicular helper T cells in peripheral blood of patients with rheumatoid arthritis. Reumatol Clin 13(6):338–343. https://doi.org/10.1016/j.reuma.2016.07.003

    Article  PubMed  Google Scholar 

  52. Cordova KN, Willis VC, Haskins K, Holers VM (2013) A citrullinated fibrinogen-specific T cell line enhances autoimmune arthritis in a mouse model of rheumatoid arthritis. J Immunol 190(4):1457–1465. https://doi.org/10.4049/jimmunol.1201517

    Article  CAS  PubMed  Google Scholar 

  53. Schmutz C, Hulme A, Burman A et al (2005) Chemokine receptors in the rheumatoid synovium: upregulation of CXCR5. Arthritis Res Ther 7(2):R217–229. https://doi.org/10.1186/ar1475

    Article  CAS  PubMed  Google Scholar 

  54. Chu Y, Wang F, Zhou M, Chen L, Lu Y (2014) A preliminary study on the characterization of follicular helper T (Tfh) cells in rheumatoid arthritis synovium. Acta Histochem 116(3):539–543. https://doi.org/10.1016/j.acthis.2013.10.009

    Article  CAS  PubMed  Google Scholar 

  55. Rao DA, Gurish MF, Marshall JL et al (2017) Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542(7639):110–114. https://doi.org/10.1038/nature20810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhang F, Wei K, Slowikowski K et al (2019) Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol 20(7):928–942. https://doi.org/10.1038/s41590-019-0378-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Manzo A, Vitolo B, Humby F et al (2008) Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint. Arthritis Rheum 58(11):3377–3387. https://doi.org/10.1002/art.23966

    Article  CAS  PubMed  Google Scholar 

  58. Rao DA (2018) T cells that help B cells in chronically inflamed tissues. Front Immunol 9:1924. https://doi.org/10.3389/fimmu.2018.01924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Yoshitomi H, Kobayashi S, Miyagawa-Hayashino A et al (2018) Human Sox4 facilitates the development of CXCL13-producing helper T cells in inflammatory environments. Nat Commun 9(1):3762. https://doi.org/10.1038/s41467-018-06187-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Donlin LT, Rao DA, Wei K et al (2018) Methods for high-dimensional analysis of cells dissociated from cryopreserved synovial tissue. Arthritis Res Ther 20(1):139. https://doi.org/10.1186/s13075-018-1631-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sakuraba K, Oyamada A, Fujimura K et al (2016) Interleukin-21 signaling in B cells, but not in T cells, is indispensable for the development of collagen-induced arthritis in mice. Arthritis Res Ther 18:188. https://doi.org/10.1186/s13075-016-1086-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Jang E, Cho SH, Park H, Paik DJ, Kim JM, Youn J (2009) A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+CD25- T cell expansion is essential for the development of arthritis in autoimmune K/BxN mice. J Immunol 182(8):4649–4656. https://doi.org/10.4049/jimmunol.0804350

    Article  CAS  PubMed  Google Scholar 

  63. Hirota K, Hashimoto M, Ito Y et al (2018) Autoimmune Th17 cells induced synovial stromal and innate lymphoid cell secretion of the cytokine GM-CSF to initiate and augment autoimmune arthritis. Immunity 48(6):1220–1232. https://doi.org/10.1016/j.immuni.2018.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Nurieva R, Yang XO, Martinez G et al (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448(7152):480–483. https://doi.org/10.1038/nature05969

    Article  CAS  PubMed  Google Scholar 

  65. Block KE, Huang H (2013) The cellular source and target of IL-21 in K/BxN autoimmune arthritis. J Immunol 191(6):2948–2955. https://doi.org/10.4049/jimmunol.1301173

    Article  CAS  PubMed  Google Scholar 

  66. Zhang Y, Li Y, Lv TT, Yin ZJ, Wang XB (2015) Elevated circulating Th17 and follicular helper CD4(+) T cells in patients with rheumatoid arthritis. APMIS 123(8):659–666. https://doi.org/10.1111/apm.12399

    Article  CAS  PubMed  Google Scholar 

  67. Liu R, Wu Q, Su D et al (2012) A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis Res Ther 14(6):R255. https://doi.org/10.1186/ar4100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Reyes-Perez IV, Sanchez-Hernandez PE, Munoz-Valle JF et al (2019) Cytokines (IL-15, IL-21, and IFN-gamma) in rheumatoid arthritis: association with positivity to autoantibodies (RF, anti-CCP, anti-MCV, and anti-PADI4) and clinical activity. Clin Rheumatol 38(11):3061–3071. https://doi.org/10.1007/s10067-019-04681-4

    Article  PubMed  Google Scholar 

  69. Dam EM, Maier AC, Hocking AM, Carlin J, Ng B, Buckner JH (2018) Increased binding of specificity protein 1 to the IL21R promoter in B Cells results in enhanced B cell responses in rheumatoid arthritis. Front Immunol 9:1978. https://doi.org/10.3389/fimmu.2018.01978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Jungel A, Distler JH, Kurowska-Stolarska M et al (2004) Expression of interleukin-21 receptor, but not interleukin-21, in synovial fibroblasts and synovial macrophages of patients with rheumatoid arthritis. Arthritis Rheum 50(5):1468–1476. https://doi.org/10.1002/art.20218

    Article  CAS  PubMed  Google Scholar 

  71. Kuchen S, Robbins R, Sims GP et al (2007) Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4+ T cell-B cell collaboration. J Immunol 179(9):5886–5896. https://doi.org/10.4049/jimmunol.179.9.5886

    Article  CAS  PubMed  Google Scholar 

  72. Xing R, Jin Y, Sun L et al (2016) Interleukin-21 induces migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis. Clin Exp Immunol 184(2):147–158. https://doi.org/10.1111/cei.12751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Xing R, Yang L, Jin Y et al (2016) Interleukin-21 induces proliferation and proinflammatory cytokine profile of fibroblast-like synoviocytes of patients with rheumatoid arthritis. Scand J Immunol 83(1):64–71. https://doi.org/10.1111/sji.12396

    Article  CAS  PubMed  Google Scholar 

  74. Fillatreau S, Gray D (2003) T cell accumulation in B cell follicles is regulated by dendritic cells and is independent of B cell activation. J Exp Med 197(2):195–206. https://doi.org/10.1084/jem.20021750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Liu YJ, Joshua DE, Williams GT, Smith CA, Gordon J, MacLennan IC (1989) Mechanism of antigen-driven selection in germinal centres. Nature 342(6252):929–931. https://doi.org/10.1038/342929a0

    Article  CAS  PubMed  Google Scholar 

  76. Cicalese MP, Gerosa J, Baronio M et al (2018) Circulating follicular helper and follicular regulatory T cells are severely compromised in human CD40 deficiency: a case report. Front Immunol 9:1761. https://doi.org/10.3389/fimmu.2018.01761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Peters AL, Stunz LL, Bishop GA (2009) CD40 and autoimmunity: the dark side of a great activator. Semin Immunol 21(5):293–300. https://doi.org/10.1016/j.smim.2009.05.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Roman-Fernandez IV, Garcia-Chagollan M, Cerpa-Cruz S et al (2019) Assessment of CD40 and CD40L expression in rheumatoid arthritis patients, association with clinical features and DAS28. Clin Exp Med. https://doi.org/10.1007/s10238-019-00568-5

    Article  PubMed  Google Scholar 

  79. Guo Y, Walsh AM, Fearon U et al (2017) CD40L-dependent pathway is active at various stages of rheumatoid arthritis disease progression. J Immunol 198(11):4490–4501. https://doi.org/10.4049/jimmunol.1601988

    Article  CAS  PubMed  Google Scholar 

  80. Rodriguez-Barbosa JI, Fernandez-Renedo C, Moral AMB, Buhler L, Del Rio ML (2017) T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway. Cell Mol Immunol 14(6):497–510. https://doi.org/10.1038/cmi.2015.101

    Article  CAS  PubMed  Google Scholar 

  81. Nicholson SM, Casey KA, Gunsior M et al (2020) The enhanced immunopharmacology of VIB4920, a novel Tn3 fusion protein and CD40L antagonist, and assessment of its safety profile in cynomolgus monkeys. Br J Pharmacol 177(5):1061–1076. https://doi.org/10.1111/bph.14897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Karnell JL, Albulescu M, Drabic S et al (2019) A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aar6584

    Article  PubMed  Google Scholar 

  83. Roser-Page S, Vikulina T, Yu K, McGee-Lawrence ME, Weitzmann MN (2018) Neutralization of CD40 ligand costimulation promotes bone formation and accretion of vertebral bone mass in mice. Rheumatology (Oxford) 57(6):1105–1114. https://doi.org/10.1093/rheumatology/kex525

    Article  CAS  Google Scholar 

  84. Boumpas DT, Furie R, Manzi S et al (2003) A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 48(3):719–727. https://doi.org/10.1002/art.10856

    Article  CAS  PubMed  Google Scholar 

  85. Visvanathan S, Daniluk S, Ptaszyński R et al (2019) Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and biomarker variables in patients with active rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase IIa study. Ann Rheum Dis 78(6):754–760. https://doi.org/10.1136/annrheumdis-2018-214729

    Article  CAS  PubMed  Google Scholar 

  86. Dong C, Nurieva RI (2003) Regulation of immune and autoimmune responses by ICOS. J Autoimmun 21(3):255–260

    Article  Google Scholar 

  87. Robertson N, Engelhardt KR, Morgan NV et al (2015) Astute clinician report: a novel 10 bp Frameshift deletion in exon 2 of ICOS causes a combined immunodeficiency associated with an enteritis and hepatitis. J Clin Immunol 35(7):598–603. https://doi.org/10.1007/s10875-015-0193-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Uwadiae FI, Pyle CJ, Walker SA, Lloyd CM, Harker JA (2019) Targeting the ICOS/ICOS-L pathway in a mouse model of established allergic asthma disrupts T follicular helper cell responses and ameliorates disease. Allergy 74(4):650–662. https://doi.org/10.1111/all.13602

    Article  CAS  PubMed  Google Scholar 

  89. Cheng LE, Amoura Z, Cheah B et al (2018) Brief report: a randomized, double-blind, parallel-group, placebo-controlled, multiple-dose study to evaluate AMG 557 in patients with systemic lupus erythematosus and active lupus arthritis. Arthritis Rheumatol 70(7):1071–1076. https://doi.org/10.1002/art.40479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dinesh P, Rasool M (2018) Multifaceted role of IL-21 in rheumatoid arthritis: Current understanding and future perspectives. J Cell Physiol 233(5):3918–3928. https://doi.org/10.1002/jcp.26158

    Article  CAS  PubMed  Google Scholar 

  91. Choi JY, Seth A, Kashgarian M et al (2017) Disruption of pathogenic cellular networks by IL-21 blockade leads to disease amelioration in murine lupus. J Immunol 198(7):2578–2588. https://doi.org/10.4049/jimmunol.1601687

    Article  CAS  PubMed  Google Scholar 

  92. Young DA, Hegen M, Ma HL et al (2007) Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum 56(4):1152–1163. https://doi.org/10.1002/art.22452

    Article  CAS  PubMed  Google Scholar 

  93. Ignatenko S, Skrumsager BK, Mouritzen U (2016) Safety, PK, and PD of recombinant anti-interleukin-21 monoclonal antibody in a first-in-human trial. Int J Clin Pharmacol Ther 54(4):243–252. https://doi.org/10.5414/cp202474

    Article  CAS  PubMed  Google Scholar 

  94. Cañete J, Leszczynski P, Riisbro R, Frederiksen K (2014) Efficacy and safety of NNC01140006, an anti-IL-21 monoclonal antibody, in patients with active rheumatoid arthritis Arthritis Rheumatol 66: 947

  95. Robak T, Gladalska A, Stepien H, Robak E (1998) Serum levels of interleukin-6 type cytokines and soluble interleukin-6 receptor in patients with rheumatoid arthritis. Mediators Inflamm 7(5):347–353. https://doi.org/10.1080/09629359890875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Houssiau FA, Devogelaer JP, Van Damme J, de Deuxchaisnes CN, Van Snick J (1988) Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum 31(6):784–788

    Article  CAS  Google Scholar 

  97. Straub RH, Muller-Ladner U, Lichtinger T, Scholmerich J, Menninger H, Lang B (1997) Decrease of interleukin 6 during the first 12 months is a prognostic marker for clinical outcome during 36 months treatment with disease-modifying anti-rheumatic drugs. Br J Rheumatol 36(12):1298–1303

    Article  CAS  Google Scholar 

  98. Gottenberg JE, Dayer JM, Lukas C et al (2012) Serum IL-6 and IL-21 are associated with markers of B cell activation and structural progression in early rheumatoid arthritis: results from the ESPOIR cohort. Ann Rheum Dis 71(7):1243–1248. https://doi.org/10.1136/annrheumdis-2011-200975

    Article  CAS  PubMed  Google Scholar 

  99. Niu Q, Huang ZC, Wu XJ et al (2018) Enhanced IL-6/phosphorylated STAT3 signaling is related to the imbalance of circulating T follicular helper/T follicular regulatory cells in patients with rheumatoid arthritis. Arthritis Res Ther 20(1):200. https://doi.org/10.1186/s13075-018-1690-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Burmester GR, Rigby WF, van Vollenhoven RF et al (2016) Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis 75(6):1081–1091. https://doi.org/10.1136/annrheumdis-2015-207628

    Article  CAS  PubMed  Google Scholar 

  101. Burmester GR, Rigby WF, van Vollenhoven RF et al (2017) Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naive patients with early rheumatoid arthritis: 2-year clinical and radiographic results from the randomised, placebo-controlled FUNCTION trial. Ann Rheum Dis 76(7):1279–1284. https://doi.org/10.1136/annrheumdis-2016-210561

    Article  CAS  PubMed  Google Scholar 

  102. Huizinga TW, Fleischmann RM, Jasson M et al (2014) Sarilumab, a fully human monoclonal antibody against IL-6Ralpha in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis 73(9):1626–1634. https://doi.org/10.1136/annrheumdis-2013-204405

    Article  CAS  PubMed  Google Scholar 

  103. Strand V, Kosinski M, Chen CI et al (2016) Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial. Arthritis Res Ther 18:198. https://doi.org/10.1186/s13075-016-1096-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Muyldermans S (2013) Nanobodies: natural single-domain antibodies. Annu Rev Biochem 82:775–797. https://doi.org/10.1146/annurev-biochem-063011-092449

    Article  CAS  PubMed  Google Scholar 

  105. Van Roy M, Ververken C, Beirnaert E et al (2015) The preclinical pharmacology of the high affinity anti-IL-6R Nanobody(R) ALX-0061 supports its clinical development in rheumatoid arthritis. Arthritis Res Ther 17:135. https://doi.org/10.1186/s13075-015-0651-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Holz J-B, Sargentini-Maier L, De Bruyn S et al (2013) OP0043 twenty-four weeks of treatment with a novel anti-IL-6 receptor nanobody® (ALX-0061) resulted in 84% ACR20 improvement and 58% DAS28 remission in a phase I/Ii study in RA. Ann Rheum Dis 72(Suppl 3):A64–A64. https://doi.org/10.1136/annrheumdis-2013-eular.248

    Article  Google Scholar 

  107. Genovese MC, Fleischmann R, Furst D et al (2014) Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study. Ann Rheum Dis 73(9):1607–1615. https://doi.org/10.1136/annrheumdis-2013-204760

    Article  CAS  PubMed  Google Scholar 

  108. Takeuchi T, Tanaka Y, Yamanaka H et al (2016) Efficacy and safety of olokizumab in Asian patients with moderate-to-severe rheumatoid arthritis, previously exposed to anti-TNF therapy: results from a randomized phase II trial. Mod Rheumatol 26(1):15–23. https://doi.org/10.3109/14397595.2015.1074648

    Article  CAS  PubMed  Google Scholar 

  109. Takeuchi T, Thorne C, Karpouzas G et al (2017) Sirukumab for rheumatoid arthritis: the phase III SIRROUND-D study. Ann Rheum Dis 76(12):2001–2008. https://doi.org/10.1136/annrheumdis-2017-211328

    Article  CAS  PubMed  Google Scholar 

  110. Aletaha D, Bingham CO 3rd, Tanaka Y et al (2017) Efficacy and safety of sirukumab in patients with active rheumatoid arthritis refractory to anti-TNF therapy (SIRROUND-T): a randomised, double-blind, placebo-controlled, parallel-group, multinational, phase 3 study. Lancet 389(10075):1206–1217. https://doi.org/10.1016/s0140-6736(17)30401-4

    Article  CAS  PubMed  Google Scholar 

  111. Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S (2012) STAT5 is a potent negative regulator of TFH cell differentiation. J Exp Med 209(2):243–250. https://doi.org/10.1084/jem.20111174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Cai G, Nie X, Zhang W et al (2012) A regulatory role for IL-10 receptor signaling in development and B cell help of T follicular helper cells in mice. J Immunol 189(3):1294–1302. https://doi.org/10.4049/jimmunol.1102948

    Article  CAS  PubMed  Google Scholar 

  113. Ballesteros-Tato A, Leon B, Graf BA et al (2012) Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36(5):847–856. https://doi.org/10.1016/j.immuni.2012.02.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Nurieva RI, Podd A, Chen Y et al (2012) STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J Biol Chem 287(14):11234–11239. https://doi.org/10.1074/jbc.M111.324046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kosmaczewska A, Ciszak L, Swierkot J, Szteblich A, Kosciow K, Frydecka I (2015) Exogenous IL-2 controls the balance in Th1, Th17, and Treg cell distribution in patients with progressive rheumatoid arthritis treated with TNF-alpha inhibitors. Inflammation 38(2):765–774. https://doi.org/10.1007/s10753-014-9987-x

    Article  CAS  PubMed  Google Scholar 

  116. Wu R, Li N, Zhao X et al (2020) Low-dose Interleukin-2: biology and therapeutic prospects in rheumatoid arthritis. Autoimmun Rev 19(10):102645. https://doi.org/10.1016/j.autrev.2020.102645

    Article  CAS  PubMed  Google Scholar 

  117. Elsner RA, Shlomchik MJ (2019) IL-12 blocks Tfh cell differentiation during salmonella infection, thereby contributing to germinal center suppression. Cell Rep 29(9):2796–2809 e2795. https://doi.org/10.1016/j.celrep.2019.10.069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Reighard SD, Cranert SA, Rangel KM et al (2020) Therapeutic Targeting of follicular T cells with chimeric antigen receptor-expressing natural killer cells. Cell Rep Med. https://doi.org/10.1016/j.xcrm.2020.100003

    Article  PubMed  PubMed Central  Google Scholar 

  119. King C (2020) CAR NK cell therapy for T follicular helper cells. Cell Rep Med 1(1):100009. https://doi.org/10.1016/j.xcrm.2020.100009

    Article  PubMed  PubMed Central  Google Scholar 

  120. Linterman MA, Pierson W, Lee SK et al (2011) Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 17(8):975–982. https://doi.org/10.1038/nm.2425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Li L, Yang SH, Yao Y et al (2016) Block of both TGF-beta and IL-2 signaling impedes Neurophilin-1(+) regulatory T cell and follicular regulatory T cell development. Cell Death Dis 7(10):e2439. https://doi.org/10.1038/cddis.2016.348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ding T, Niu H, Zhao X, Gao C, Li X, Wang C (2019) T-follicular regulatory cells: potential therapeutic targets in rheumatoid arthritis. Front Immunol 10:2709. https://doi.org/10.3389/fimmu.2019.02709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Fukuyo S, Nakayamada S, Iwata S, Kubo S, Saito K, Tanaka Y (2017) Abatacept therapy reduces CD28+CXCR5+ follicular helper-like T cells in patients with rheumatoid arthritis. Clin Exp Rheumatol 35(4):562–570

    PubMed  Google Scholar 

  124. Azizov V, Dietel K, Steffen F et al (2020) Ethanol consumption inhibits T(FH) cell responses and the development of autoimmune arthritis. Nat Commun 11(1):1998. https://doi.org/10.1038/s41467-020-15855-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81771759 and 82071835), Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant NO. KYCX20_3050), and Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine, Affiliated People’s Hospital, Jiangsu University, Zhenjiang, 212002, China

    Jian Lu, Huiyong Peng & Shengjun Wang

  2. Institute of Laboratory Medicine, Jiangsu Key Laboratory for Laboratory Medicine, Jiangsu University School of Medicine, Zhenjiang, China

    Jian Lu, Jing Wu, Xueli Xia & Shengjun Wang

Authors
  1. Jian Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xueli Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huiyong Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shengjun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JL drafted the manuscript. JW, XX, and HP discussed and revised the manuscript. SW designed the study and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Huiyong Peng or Shengjun Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lu, J., Wu, J., Xia, X. et al. Follicular helper T cells: potential therapeutic targets in rheumatoid arthritis. Cell. Mol. Life Sci. 78, 5095–5106 (2021). https://doi.org/10.1007/s00018-021-03839-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-021-03839-1

Keywords

Search

Navigation