Tregs in SLE: an Update

  • Antonio La Cava
Systemic Lupus Erythematosus (G Tsokos, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Systemic Lupus Erythematosus


Purpose of Review

There has been great interest in understanding why T regulatory cells (Tregs) are reduced in number and/or in function in several autoimmune diseases including systemic lupus erythematosus (SLE). Although research has provided some answers, there is still much to learn.

Recent Findings

Recent investigations on the mechanisms responsible for the impairment of the Tregs in SLE have identified relevant abnormalities in cellular and molecular pathways that have been instrumental in the design of studies in animal models and in the development of pilot immunotherapeutic studies in lupus patients.


We review the progress made in the field in the last 5 years, discussing the mechanistic studies, together with the preclinical and clinical works that are moving forward the understanding of the physiopathology of Tregs in SLE.


SLE T regulatory cells 


Compliance with Ethical Standards

Conflict of Interest

The author declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998;188(2):287–96. Scholar
  2. 2.
    McNally A, Hill GR, Sparwasser T, Thomas R, Steptoe RJ. CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis. Proc Natl Acad Sci U S A. 2011;108(18):7529–34. Scholar
  3. 3.
    Lim HW, Hillsamer P, Banham AH, Kim CH. Cutting edge: direct suppression of B cells by CD4+CD25+ regulatory T cells. J Immunol. 2005;175(7):4180–3. Scholar
  4. 4.
    Iikuni N, Lourenço EV, Hahn BH, La Cava A. Cutting edge: regulatory T cells directly suppress B cells in systemic lupus erythematosus. J Immunol. 2009;183(3):1518–22. Scholar
  5. 5.
    Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol. 2003;3(3):253–7. Scholar
  6. 6.
    Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H, et al. TGF-β1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol. 2004;172(2):834–42. Scholar
  7. 7.
    Oida T, Xu L, Weiner HL, Kitani A, Strober W. TGF-β-mediated suppression by CD4+CD25+ T cells is facilitated by CTLA-4 signaling. J Immunol. 2006;177(4):2331–9. Scholar
  8. 8.
    La Cava A, Ebling FM, Hahn BH. Ig-reactive CD4+CD25+ T cells from tolerized (New Zealand Black x New Zealand White)F1 mice suppress in vitro production of antibodies to DNA. J Immunol. 2004;173(5):3542–8. Scholar
  9. 9.
    Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3+CD25+CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med. 2005;201(5):723–35. Scholar
  10. 10.
    Zorn E, Nelson EA, Mohseni M, Porcheray F, Kim H, Litsa D, et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood. 2006;108(5):1571–9. Scholar
  11. 11.
    Comte D, Karampetsou MP, Kis-Toth K, Yoshida N, Bradley SJ, Mizui M, et al. Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus. Proc Natl Acad Sci U S A. 2016;113(33):9321–6. Scholar
  12. 12.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61. Scholar
  13. 13.
    Tran DQ, Ramsey H, Shevach EM. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-β dependent but does not confer a regulatory phenotype. Blood. 2007;110(8):2983–90. Scholar
  14. 14.
    Baron U, Floess S, Wieczorek G, Baumann K, Grutzkau A, Dong J, et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3+ conventional T cells. Eur J Immunol. 2007;37(9):2378–89. Scholar
  15. 15.
    Scalapino KJ, Tang Q, Bluestone JA, Bonyhadi ML, Daikh DI. Suppression of disease in New Zealand Black/New Zealand White lupus-prone mice by adoptive transfer of ex vivo expanded regulatory T cells. J Immunol. 2006;177(3):1451–9. Scholar
  16. 16.
    Humrich JY, Morbach H, Undeutsch R, Enghard P, Rosenberger S, Weigert O, et al. Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus. Proc Natl Acad Sci U S A. 2010;107(1):204–9. Scholar
  17. 17.
    Giang S, La Cava A. Regulatory T cells in SLE: biology and use in treatment. Curr Rheumatol Rep. 2016;18(11):67. Scholar
  18. 18.
    Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899–911. Scholar
  19. 19.
    Pan X, Yuan X, Zheng Y, Wang W, Shan J, Lin F, et al. Increased CD45RA+FoxP3low regulatory T cells with impaired suppressive function in patients with systemic lupus erythematosus. PLoS One. 2012;7(4):e34662. Scholar
  20. 20.
    Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol. 2010;184(7):3433–41. Scholar
  21. 21.
    Kim YC, Bhairavabhotla R, Yoon J, Golding A, Thornton AM, Tran DQ, et al. Oligodeoxynucleotides stabilize Helios expressing Foxp3+ human T regulatory cells during in vitro expansion. Blood. 2012;119(12):2810–8. Scholar
  22. 22.
    Alexander T, Sattler A, Templin L, Kohler S, Gross C, Meisel A, et al. Foxp3+Helios+ regulatory T cells are expanded in active systemic lupus erythematosus. Ann Rheum Dis. 2013;72(9):1549–58. Scholar
  23. 23.
    Okamura T, Sumitomo S, Morita K, Iwasaki Y, Inoue M, Nakachi S, et al. TGF-β3-expressing CD4+CD25LAG3+ regulatory T cells control humoral immune responses. Nat Commun. 2015;6:6329.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    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. Scholar
  25. 25.
    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. Scholar
  26. 26.
    Fujio K, Okamura T, Sumitomo S, Yamamoto K. Regulatory cell subsets in the control of autoantibody production related to systemic autoimmunity. Ann Rheum Dis. 2013;72(Suppl 2):ii85–9. Scholar
  27. 27.
    Nocentini G, Alunno A, Petrillo MG, Bistoni O, Bartoloni E, Caterbi S, et al. Expansion of regulatory GITR+CD25low/-CD4+ T cells in systemic lupus erythematosus patients. Arthritis Res Ther. 2014;16(5):444. Scholar
  28. 28.
    Miyara M, Chader D, Sage E, Sugiyama D, Nishikawa H, Bouvry D, et al. Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3high regulatory T cells in humans. Proc Natl Acad Sci U S A. 2015;112(23):7225–30. Scholar
  29. 29.
    La Cava A. Survive to fight: effector Treg cells in systemic lupus erythematosus. Arthritis Rheumatol. 2016;68(6):1327–9. Scholar
  30. 30.
    Chandrasekaran U, Yi W, Gupta S, Weng CH, Giannopoulou E, Chinenov Y, et al. Regulation of effector Treg cells in murine lupus. Arthritis Rheumatol. 2016;68(6):1454–66. Scholar
  31. 31.
    Xu A, Liu Y, Chen W, Wang J, Xue Y, Huang F, et al. TGF-β-induced regulatory T cells directly suppress B cell responses through a noncytotoxic mechanism. J Immunol. 2016;196(9):3631–41. Scholar
  32. 32.
    Liu Y, Liu A, Iikuni N, Xu H, Shi FD, La Cava A. Regulatory CD4+ T cells promote B cell anergy in murine lupus. J Immunol. 2014;192(9):4069–73. Scholar
  33. 33.
    Wong M, La Cava A, Hahn BH. Blockade of programmed death-1 in young (New Zealand Black x New Zealand White)F1 mice promotes the suppressive capacity of CD4+ regulatory T cells protecting from lupus-like disease. J Immunol. 2013;190(11):5402–10. Scholar
  34. 34.
    Lan Q, Zhou X, Fan H, Chen M, Wang J, Ryffel B, et al. Polyclonal CD4+Foxp3+ Treg cells induce TGFβ-dependent tolerogenic dendritic cells that suppress the murine lupus-like syndrome. J Mol Cell Biol. 2012;4(6):409–19. Scholar
  35. 35.
    Koga T, Ichinose K, Mizui M, Crispín JC, Tsokos GC. Calcium/calmodulin-dependent protein kinase IV suppresses IL-2 production and regulatory T cell activity in lupus. J Immunol. 2012;189:3490–6.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    •• Apostolidis SA, Rodríguez-Rodríguez N, Suárez-Fueyo A, Dioufa N, Ozcan E, Crispín JC, et al. Phosphatase PP2A is requisite for the function of regulatory T cells. Nat Immunol. 2016;17(5):556–64. This study revealed the importance of the serine-threonine phosphatase PP2A in the function of Tregs and in the prevention of autoimmunity. Tregs were found to have high PP2A activity, and the ablation of the PP2A complex in Tregs led to development of severe autoimmune manifestations. Scholar
  37. 37.
    Sharabi A, Kasper IR, Tsokos GC. The serine/threonine protein phosphatase 2A controls autoimmunity. Clin Immunol. 2018.Google Scholar
  38. 38.
    Wang X, Qiao Y, Yang L, Song S, Han Y, Tian Y, Ding M, Jin H, Shao F, Liu A. Leptin levels in patients with systemic lupus erythematosus inversely correlate with regulatory T cell frequency. Lupus. 2017;26:1401–6. Scholar
  39. 39.
    Lourenço EV, Liu A, Matarese G, La Cava A. Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation. Proc Natl Acad Sci U S A. 2016;113(38):10637–42. Scholar
  40. 40.
    Liu Y, Yu Y, Matarese G, La Cava A. Cutting edge: fasting-induced hypoleptinemia expands functional regulatory T cells in systemic lupus erythematosus. J Immunol. 2012;188(5):2070–3. Scholar
  41. 41.
    Yu Y, Liu Y, Shi FD, Zou H, Hahn BH, La Cava A. Tolerance induced by anti-DNA Ig peptide in (NZB × NZW)F1 lupus mice impinges on the resistance of effector T cells to suppression by regulatory T cells. Clin Immunol. 2012;142(3):291–5. Scholar
  42. 42.
    Liu A, La Cava A. Epigenetic dysregulation in systemic lupus erythematosus. Autoimmunity. 2014;47(4):215–9. Scholar
  43. 43.
    Amarilyo G, La Cava A. miRNA in systemic lupus erythematosus. Clin Immunol. 2012;144(1):26–31. Scholar
  44. 44.
    Wang H, Peng W, Ouyang X, Li W, Dai Y. Circulating microRNAs as candidate biomarkers in patients with systemic lupus erythematosus. Transl Res. 2012;160(3):198–206. Scholar
  45. 45.
    • Pan W, Zhu S, Dai D, Liu Z, Li D, Li B, et al. MiR-125a targets effector programs to stabilize Treg-mediated immune homeostasis. Nat Commun. 2015;6:7096. This study identified miR-125a as a critical factor in the stabilization of Tregs and the control of autoimmune disease. Scholar
  46. 46.
    Garchow B, Kiriakidou M. MicroRNA-21 deficiency protects from lupus-like autoimmunity in the chronic graft-versus-host disease model of systemic lupus erythematosus. Clin Immunol. 2016;162:100–6. Scholar
  47. 47.
    Mizui M, Koga T, Lieberman LA, Beltran J, Yoshida N, Johnson MC, et al. IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4CD8 IL-17-producing T cells. J Immunol. 2014;193(5):2168–77. Scholar
  48. 48.
    • von Spee-Mayer C, Siegert E, Abdirama D, Rose A, Klaus A, Alexander T, et al. Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann Rheum Dis. 2016;75(7):1407–15. This study showed that treatment of a small number of SLE patients with a low-dose IL-2 regimen expanded functional Tregs in vivo . Scholar
  49. 49.
    • He J, Zhang X, Wei Y, Sun X, Chen Y, Deng J, et al. Low-dose interleukin-2 treatment selectively modulates CD4+ T cell subsets in patients with systemic lupus erythematosus. Nat Med. 2016;22(9):991–3. This study showed that treatment of 38 lupus patients with low-dose IL-2 resulted in the reductions of disease activity in all patients. The findings associated with increased Tregs frequency and reduced Tfh and Th17 cell responses. However, the results were not conclusive due to limitations in the study including the recruitment of the control group after end of treatment in the experimental group. Scholar
  50. 50.
    Lai ZW, Hanczko R, Bonilla E, Caza TN, Clair B, Bartos A, et al. N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2012;64(9):2937–46. Scholar
  51. 51.
    Kato H, Perl A. Mechanistic target of rapamycin complex 1 expands Th17 and CD4CD8 double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus. J Immunol. 2014;192(9):4134–44. Scholar
  52. 52.
    Lai ZW, Borsuk R, Shadakshari A, Yu J, Dawood M, Garcia R, et al. Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus. J Immunol. 2013;191(5):2236–46. Scholar
  53. 53.
    Mathian A, Jouenne R, Chader D, Cohen-Aubart F, Haroche J, Fadlallah J, et al. Regulatory T cell responses to high-dose methylprednisolone in active systemic lupus erythematosus. PLoS One. 2015;10(12):e0143689. Scholar
  54. 54.
    Weigert O, von Spee C, Undeutsch R, Kloke L, Humrich JY, Riemekasten G. CD4+Foxp3+ regulatory T cells prolong drug-induced disease remission in (NZB x NZW)F1 lupus mice. Arthritis Res Ther. 2013;15(1):R35. Scholar
  55. 55.
    Qiao G, Yang L, Li Z, Williams JW, Zhang J. A77 1726, the active metabolite of leflunomide, attenuates lupus nephritis by promoting the development of regulatory T cells and inhibiting IL-17-producing double negative T cells. Clin Immunol. 2015;157(2):166–74. Scholar
  56. 56.
    Koga T, Mizui M, Yoshida N, Otomo K, Lieberman LA, Crispín JC, et al. KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase IV, promotes generation and function of Foxp3+ regulatory T cells in MRL/lpr mice. Autoimmunity. 2014;47(7):445–50. Scholar
  57. 57.
    Zhang L, Bertucci AM, Ramsey-Goldman R, Harsha-Strong ER, Burt RK, Datta SK. Major pathogenic steps in human lupus can be effectively suppressed by nucleosomal histone peptide epitope-induced regulatory immunity. Clin Immunol. 2013;149(3):365–78. Scholar
  58. 58.
    Sthoeger Z, Zinger H, Sharabi A, Asher I, Mozes E. The tolerogenic peptide, hCDR1, down-regulates the expression of interferon-α in murine and human systemic lupus erythematosus. PLoS One. 2013;8(3):e60394. Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of MedicineUniversity of California Los AngelesLos AngelesUSA

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