Sustained low-dose interleukin-2 therapy alleviates pathogenic humoral immunity via elevating the Tfr/Tfh ratio in lupus
Kaili Liang, Jing He, Yunbo Wei, Qunxiong Zeng, Dongcheng Gong, Jiahuan Qin, Huihua Ding, Zhian Chen, Ping Zhou, Peng Niu, Qian Chen, Chenguang Ding, Liangjing Lu, Xiao-Xiang Chen, Zhanguo Li, Nan Shen, Di Yu, Jun Deng, Kaili Liang, Jing He, Yunbo Wei, Qunxiong Zeng, Dongcheng Gong, Jiahuan Qin, Huihua Ding, Zhian Chen, Ping Zhou, Peng Niu, Qian Chen, Chenguang Ding, Liangjing Lu, Xiao-Xiang Chen, Zhanguo Li, Nan Shen, Di Yu, Jun Deng
Abstract
Objectives: Low-dose interleukin-2 (IL-2) has shown promising clinical benefits in the treatment of systemic lupus erythematosus (SLE), but how this therapy alleviates pathogenic humoral immunity remains not well understood. The dilemma is that IL-2 can suppress both follicular helper and regulatory T (Tfh and Tfr) cells, which counteract each other in regulating autoantibody production.
Methods: Female NZB/W F1 mice received recombinant human IL-2 (3 × 104 IU/dose) in three treatment regimens: (1) short, daily for 7 days; (2) medium, daily for 14 days, and (3) long, every second day for 28 days. Tfh (Foxp3-CXCR5+Bcl6+), Tfr (Foxp3+CXCR5+Bcl6+), germinal centre (GC, B220+GL-7+Fas+) and antibody-secreting cell (ASC, B220-CD138+TACI+) were analysed by flow cytometry. Serum anti-dsDNA level was determined by ELISA. Kidney pathology was evaluated by H&E and immunofluorescence staining. Circulating Tfh and Tfr cells in SLE patients treated with low-dose IL-2 from a previous clinical trial (NCT02084238) was analysed.
Results: Low-dose IL-2 treatment consistently increased Tfr/Tfh ratio in mice and SLE patients, because of a stronger suppression on Tfh cells than Tfr cells. Three treatment regimens revealed distinct immunological features. Tfh suppression was observed in all regimens, but Tfr suppression and GC reduction were recorded in just medium and long regimens. Only the long treatment regimen resulted in inhibited ASC differentiation in spleen, which was accompanied by reduced anti-dsDNA titres and ameliorated kidney pathology.
Conclusion: Low-dose IL-2 therapy increases the Tfr/Tfh ratio, and a less frequent and prolonged treatment can alleviate pathogenic humoral immunity and improve renal function.
Keywords: B cell; Tfr/Tfh ratio; humoral immunity; interleukin‐2; systemic lupus erythematosus.
Conflict of interest statement
The authors declare no conflict of interest.
© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.
Figures
References
- Kaul A, Gordon C, Crow MK et al. Systemic lupus erythematosus. Nat Rev Dis Primers 2016; 2: 16039.
- Tsokos GC. Systemic lupus erythematosus. N Engl J Med 2011; 365: 2110–2121.
- Aringer M, Costenbader K, Daikh D et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis 2019; 78: 1151–1159.
- He J, Tsai LM, Leong YA et al. Circulating precursor CCR7loPD‐1hi CXCR5+CD4 + T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity 2013; 39: 770–781.
- Scharer CD, Blalock EL, Mi T et al. Epigenetic programming underpins B cell dysfunction in human SLE. Nat Immunol 2019; 20: 1071–1082.
- Yurasov S, Wardemann H, Hammersen J et al. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J Exp Med 2005; 201: 703–711.
- Luzina IG, Atamas SP, Storrer CE et al. Spontaneous formation of germinal centers in autoimmune mice. J Leukoc Biol 2001; 70: 578–584.
- Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nat Rev Immunol 2010; 10: 236–247.
- Ma K, Li J, Wang X et al. TLR4+CXCR4+ plasma cells drive nephritis development in systemic lupus erythematosus. Ann Rheum Dis 2018; 77: 1498–1506.
- Cambridge G, Leandro MJ, Teodorescu M et al. B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody profiles. Arthritis Rheum 2006; 54: 3612–3622.
- Scott DG, Rowell NR. Immunohistological studies of the kidney in systemic lupus erythematosus and systemic sclerosis using antisera to IgG, C3, fibrin, and human renal glomeruli. Ann Rheum Dis 1974; 33: 473–481.
- Arbuckle MR, McClain MT, Rubertone MV et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003; 349: 1526–1533.
- Gualtierotti R, Borghi MO, Gerosa M et al. Successful sequential therapy with rituximab and belimumab in patients with active systemic lupus erythematosus: a case series. Clin Exp Rheumatol 2018; 36: 643–647.
- Kraaij T, Kamerling SWA, de Rooij ENM et al. The NET‐effect of combining rituximab with belimumab in severe systemic lupus erythematosus. J Autoimmun 2018; 91: 45–54.
- Kraaij T, Arends EJ, van Dam LS et al. Long‐term effects of combined B‐cell immunomodulation with rituximab and belimumab in severe, refractory systemic lupus erythematosus: 2‐year results. Nephrol Dial Transplant 2020; gfaa117: 1–10. 10.1093/ndt/gfaa117. Online ahead of print.
- Doria A, Stohl W, Schwarting A et al. Efficacy and safety of subcutaneous belimumab in anti‐double‐stranded DNA‐positive, hypocomplementemic patients with systemic lupus erythematosus. Arthritis Rheumatol 2018; 70: 1256–1264.
- Vinuesa CG, Linterman MA, Yu D, MacLennan IC. Follicular helper T cells. Annu Rev Immunol 2016; 34: 335–368.
- Ueno H, Banchereau J, Vinuesa CG. Pathophysiology of T follicular helper cells in humans and mice. Nat Immunol 2015; 16: 142–152.
- Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity 2014; 41: 529–542.
- Zhang W, Zhang H, Liu S et al. Excessive CD11c+Tbet+ B cells promote aberrant TFH differentiation and affinity‐based germinal center selection in lupus. Proc Natl Acad Sci USA 2019; 116: 18550–18560.
- Choi JY, Ho JH, Pasoto SG et al. Circulating follicular helper‐like T cells in systemic lupus erythematosus: association with disease activity. Arthritis Rheumatol 2015; 67: 988–999.
- Linterman MA, Pierson W, Lee SK et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 2011; 17: 975–982.
- Chung Y, Tanaka S, Chu F et al. Follicular regulatory T cells expressing Foxp3 and Bcl‐6 suppress germinal center reactions. Nat Med 2011; 17: 983–988.
- Clement RL, Daccache J, Mohammed MT et al. Follicular regulatory T cells control humoral and allergic immunity by restraining early B cell responses. Nat Immunol 2019; 20: 1360–1371.
- Deng J, Wei Y, Fonseca VR, Graca L, Yu D. T follicular helper cells and T follicular regulatory cells in rheumatic diseases. Nat Rev Rheumatol 2019; 15: 475–490.
- Sage PT, Sharpe AH. T follicular regulatory cells in the regulation of B cell responses. Trends Immunol 2015; 36: 410–418.
- Xu B, Wang S, Zhou M 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.
- Hao H, Nakayamada S, Yamagata K et al. Conversion of T Follicular Helper Cells to T Follicular Regulatory Cells by Interleukin‐2 Through Transcriptional Regulation in Systemic Lupus Erythematosus. Arthritis Rheumatol 2021; 73: 132–142.
- Spolski R, Li P, Leonard WJ. Biology and regulation of IL‐2: from molecular mechanisms to human therapy. Nat Rev Immunol 2018; 18: 648–659.
- Koreth J, Matsuoka K, Kim HT et al. Interleukin‐2 and regulatory T cells in graft‐versus‐host disease. N Engl J Med 2011; 365: 2055–2066.
- Saadoun D, Rosenzwajg M, Joly F et al. Regulatory T‐cell responses to low‐dose interleukin‐2 in HCV‐induced vasculitis. N Engl J Med 2011; 365: 2067–2077.
- He J, Zhang X, Wei Y et al. Low‐dose interleukin‐2 treatment selectively modulates CD4+ T cell subsets in patients with systemic lupus erythematosus. Nat Med 2016; 22: 991–993.
- von Spee‐Mayer C, Siegert E, Abdirama D et al. Low‐dose interleukin‐2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann Rheum Dis 2016; 75: 1407–1415.
- Yan JJ, Lee JG, Jang JY, Koo TY, Ahn C, Yang J. IL‐2/anti‐IL‐2 complexes ameliorate lupus nephritis by expansion of CD4+CD25+Foxp3+ regulatory T cells. Kidney Int 2017; 91: 603–615.
- Ballesteros‐Tato A, Leon B, Graf BA et al. Interleukin‐2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 2012; 36: 847–856.
- Botta D, Fuller MJ, Marquez‐Lago TT et al. Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. Nat Immunol 2017; 18: 1249–1260.
- Theofilopoulos AN, Dixon FJ. Murine models of systemic lupus erythematosus. Adv Immunol 1985; 37: 269–390.
- Andrews BS, Eisenberg RA, Theofilopoulos AN et al. Spontaneous murine lupus‐like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med 1978; 148: 1198–1215.
- Mosmann TR, Yokota T, Kastelein R, Zurawski SM, Arai N, Takebe Y. Species‐specificity of T cell stimulating activities of IL 2 and BSF‐1 (IL 4): comparison of normal and recombinant, mouse and human IL 2 and BSF‐1 (IL 4). J Immunol 1987; 138: 1813–1816.
- Hu YL, Metz DP, Chung J, Siu G, Zhang M. B7RP‐1 blockade ameliorates autoimmunity through regulation of follicular helper T cells. J Immunol 2009; 182: 1421–1428.
- He J, Zhang R, Shao M et al. Efficacy and safety of low‐dose IL‐2 in the treatment of systemic lupus erythematosus: a randomised, double‐blind, placebo‐controlled trial. Ann Rheum Dis 2020; 79: 141–149.
- Humrich JY, von Spee‐Mayer C, Siegert E et al. Rapid induction of clinical remission by low‐dose interleukin‐2 in a patient with refractory SLE. Ann Rheum Dis 2015; 74: 791–792.
- Liu C, Wang D, Song Y, Lu S, Zhao J, Wang H. Increased circulating CD4+CXCR5+FoxP3+ follicular regulatory T cells correlated with severity of systemic lupus erythematosus patients. Int Immunopharmacol 2018; 56: 261–268.
- Papillion A, Powell MD, Chisolm DA et al. Inhibition of IL‐2 responsiveness by IL‐6 is required for the generation of GC‐TFH cells. Sci Immunol 2019; 4: eaaw7636.
- Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.
- Kikawada E, Lenda DM, Kelley VR. IL‐12 deficiency in MRL‐Fas lpr mice delays nephritis and intrarenal IFN‐gamma expression, and diminishes systemic pathology. J Immunol 2003; 170: 3915–3925.
Source: PubMed