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Clinical Rheumatology

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01-12-2020 | Rheumatoid Arthritis | Original Article

Interleukin-29 regulates T follicular helper cells by repressing BCL6 in rheumatoid arthritis patients

Authors: Tingshuang Xu, Tianyi Yan, Ping Li

Published in: Clinical Rheumatology | Issue 12/2020

Abstract

Introduction

We aimed to investigate whether Interleukin-29 (IL-29) directly affects T follicular helper (Tfh) cell frequency in rheumatoid arthritis (RA), which are both related to RA-specific antibody responses.

Methods

Here, we explored the effect of IL-29 on Tfh cell production in RA patients using a combination of enzyme-linked immunosorbent assay (ELISA), flow cytometry (FCM), CD4⁺ T cell culture, western blotting, and reverse transcription–polymerase chain reaction (RT-PCR).

Results

We reported that serum IL-29 levels, peripheral blood CD4⁺CXCR5⁺ Tfh cell frequency, CD4⁺CXCR5⁺CD40L⁺ Tfh cell frequency, and IL-28 receptor (IL-28Rα) and IL-10 receptor (IL-10R2) levels in peripheral blood Tfh cells were higher in RA patients than in healthy controls (HCs). Serum IL-29 levels were positively correlated with peripheral blood CD4⁺CXCR5⁺CD40L⁺ Tfh cell frequency in RA patients, and both parameters also correlated with anti-cyclic citrullinated peptide (anti-CCP) antibodies. Furthermore, we showed that IL-29 may suppress Tfh cell differentiation in RA patients partly via decreased BCL6 level through reduced STAT3 activity.

Conclusions

Taken together, our findings reveal the regulatory effect of IL-29 on Tfh cells, which participate in the pathogenesis of RA and provide new targets for its clinical treatment.

Key Points

• There is an increase in circulating Tfh cells and IL-29 levels in RA patients, which are correlated to anti-CCP antibodies levels and may be associated with RA pathogenesis.

• We show for the first time that IL-29 may contribute to RA by inhibiting Tfh cell production, through decreasing the activity of STAT3 and downregulating the expression of BCL6.

• The use of IL-29 biologics in patients with RA inhibits the production of Tfh cells, may prevent progression in patients with RA, and provides new targets for clinical treatment.

Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423:356–361CrossRefPubMed

McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219CrossRefPubMed

Firestein GS (2005) Immunologic mechanisms in the pathogenesis of rheumatoid arthritis. J Clin Rheumatol 11:S39–S44CrossRefPubMed

Wang M, Wei J, Li H, Ouyang X, Sun X, Tang Y, Chen H, Wang B, Li X (2018) Leptin upregulates peripheral CD4+ CXCR5+ ICOS+ T cells via increased IL-6 in rheumatoid arthritis patients. J Interf Cytokine Res 38:86–92CrossRef

Lebre MC, Vieira PL, Tang MW, Aarrass S, Helder B, Newsom-Davis T, Tak PP, Screaton GR (2017) Synovial IL-21/TNF-producing CD4+ T cells induce joint destruction in rheumatoid arthritis by inducing matrix metalloproteinase production by fibroblast-like synoviocytes. J Leukoc Biol 101(3):775–783CrossRefPubMed

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):103CrossRefPubMedPubMedCentral

Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B (2000) CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med 192:1553–1562CrossRefPubMedPubMedCentral

Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F, Lipp M, Förster R (2000) Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med 192:1545–1552CrossRefPubMedPubMedCentral

Fazilleau N, McHeyzer-Williams LJ, McHeyzer-Williams MG (2007) Local development of effector and memory T helper cells. Curr Opin Immunol 19:259–267CrossRefPubMed

10.

Fazilleau N, Mark L, McHeyzer-Williams LJ, McHeyzer-Williams MG (2009) Follicular helper T cells: lineage and location. Immunity 30:324–335CrossRefPubMedPubMedCentral

11.

Yu M, Cavero V, Lu Q, Li H (2015) Follicular helper T cells in rheumatoid arthritis. Clin Rheumatol 34:1489–1493CrossRefPubMed

12.

Wu H, Xu L-L, Teuscher P, Liu H, Kaplan MH, Dent AL (2015) An inhibitory role for the transcription factor Stat3 in controlling IL-4 and Bcl6 expression in follicular helper T cells. J Immunol 195:2080–2089CrossRefPubMed

13.

Crotty S (2011) Follicular helper CD4 T cells (Tfh). Annu Rev Immunol 29:621–663CrossRefPubMed

14.

Rao DA, Gurish MF, Marshall JL, Slowikowski K, Fonseka CY, Liu Y, Donlin LT, Henderson LA, Wei K, Mizoguchi F (2017) Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542:110–114CrossRefPubMedPubMedCentral

15.

Wang J, Shan Y, Jiang Z, Feng J, Li C, Ma L, Jiang Y (2013) 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 174:212–220PubMedPubMedCentral

16.

Ma J, Zhu C, Ma B, Tian J, Baidoo SE, Mao C, Wu W, Chen J, Tong J, Yang M (2012) Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis. Clin Dev Immunol 2012:1–7

17.

Coutant F (2019) Pathogenic effects of anti-citrullinated peptide antibodies in rheumatoid arthritis–role for glycosylation. Joint Bone Spine 86:562-567

18.

Xu D, Yan S, Wang H, Gu B, Sun K, Yang X, Sun B, Wang X (2015) IL-29 enhances LPS/TLR4-mediated inflammation in rheumatoid arthritis. Cell Physiol Biochem 37:27–34CrossRefPubMed

19.

Jordan W, Eskdale J, Srinivas S, Pekarek V, Kelner D, Rodia M, Gallagher G (2007) Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response. Genes Immun 8:254–261CrossRefPubMed

20.

Dumoutier L, Tounsi A, Michiels T, Sommereyns C, Kotenko SV, Renauld J-C (2004) Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-λ1 similarities with type I interferon signaling. J Biol Chem 279(31):32269–32274CrossRefPubMed

21.

Chang Q-j, Lv C, Zhao F, Xu T-s, Li P (2017) Elevated serum levels of interleukin-29 are associated with disease activity in rheumatoid arthritis patients with anti-cyclic citrullinated peptide antibodies. Tohoku J Exp Med 241:89–95CrossRefPubMed

22.

Arnett FC, Edworthy SM, Bloch DA, Mcshane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324CrossRefPubMed

23.

Prevoo M, Van'T Hof MA, Kuper H, Van Leeuwen M, Van De Putte L, Van Riel P (1995) 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 38:44–48CrossRefPubMed

24.

Witte K, Witte E, Sabat R, Wolk K (2010) IL-28A, IL-28B, and IL-29: promising cytokines with type I interferon-like properties. Cytokine Growth Factor Rev 21:237–251CrossRefPubMed

25.

Uzé G, Monneron D (2007) IL-28 and IL-29: newcomers to the interferon family. Biochimie 89:729–734CrossRefPubMed

26.

de Groen RA, Boltjes A, Hou J, Liu BS, McPhee F, Friborg J, Janssen HL, Boonstra A (2015) IFN-λ-mediated IL-12 production in macrophages induces IFN-γ production in human NK cells. Eur J Immunol 45:250–259CrossRefPubMed

27.

Hou W, Wang X, Ye L, Zhou L, Yang Z-Q, Riedel E, Ho W-Z (2009) Lambda interferon inhibits human immunodeficiency virus type 1 infection of macrophages. J Virol 83:3834–3842CrossRefPubMedPubMedCentral

28.

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 31:491–501CrossRefPubMed

29.

Zhu Y, Zou L, Liu Y-C (2015) T follicular helper cells, T follicular regulatory cells and autoimmunity. Int Immunol 28:173–179CrossRefPubMedPubMedCentral

30.

Rashu R, Bhuiyan TR, Hoq MR, Hossain L, Paul A, Khan AI, Chowdhury F, Harris JB, Ryan ET, Calderwood SB, Weil AA, Qadri F (2019) Cognate T and B cell interaction and association of follicular helper T cells with B cell responses in Vibrio cholerae O1 infected Bangladeshi adults. Microbes Infect 21:176–183CrossRefPubMed

31.

Hollister K, Kusam S, Wu H, Clegg N, Mondal A, Sawant DV, Dent AL (2013) Insights into the role of Bcl6 in follicular Th cells using a new conditional mutant mouse model. J Immunol 191:3705–3711CrossRefPubMed

32.

Lahmann A et al (2019) Bach2 controls T follicular helper cells by direct repression of Bcl-6. J Immunol 202:2229-2239

33.

Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, Wang Y-H, Dong C (2009) Bcl6 mediates the development of T follicular helper cells. Science 325:1001–1005CrossRefPubMedPubMedCentral

34.

Raybuck AL, Cho SH, Li J, Rogers MC, Lee K, Williams CL, Shlomchik M, Thomas JW, Chen J, Williams JV (2018) B cell–intrinsic mTORC1 promotes germinal center–defining transcription factor gene expression, somatic hypermutation, and memory B cell generation in humoral immunity. J Immunol 200:2627–2639CrossRefPubMed

35.

Zhu Z, Wang S, Zhu J, Yang Q, Dong H, Huang J (2016) MicroRNA-544 down-regulates both Bcl6 and Stat3 to inhibit tumor growth of human triple negative breast cancer. Biol Chem 397:1087–1095CrossRefPubMed

36.

Amet T, Son YM, Jiang L, Cheon IS, Huang S, Gupta SK, Dent AL, Montaner LJ, Yu Q, Sun J (2017) BCL6 represses antiviral resistance in follicular T helper cells. J Leukoc Biol 102:527–536CrossRefPubMedPubMedCentral

Title: Interleukin-29 regulates T follicular helper cells by repressing BCL6 in rheumatoid arthritis patients
Authors: Tingshuang Xu
Tianyi Yan
Ping Li
Publication date: 01-12-2020
Publisher: Springer International Publishing
Keyword: Rheumatoid Arthritis
Published in: Clinical Rheumatology / Issue 12/2020
Print ISSN: 0770-3198
Electronic ISSN: 1434-9949
DOI: https://doi.org/10.1007/s10067-020-05151-y

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Interleukin-29 regulates T follicular helper cells by repressing BCL6 in rheumatoid arthritis patients

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Conclusions

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