Balance between Regulatory T and Th17 Cells in Systemic Lupus Erythematosus: The Old and the New

Pathogenic mechanisms underlying the development of systemic lupus erythematosus (SLE) are very complex and not yet entirely clarified. However, the pivotal role of T lymphocytes in the induction and perpetuation of aberrant immune response is well established. Among T cells, IL-17 producing T helper (Th17) cells and regulatory T (Treg) cells represent an intriguing issue to be addressed in SLE pathogenesis, since an imbalance between the two subsets has been observed in the course of the disease. Treg cells appear to be impaired and therefore unable to counteract autoreactive T lymphocytes. Conversely, Th17 cells accumulate in target organs contributing to local IL-17 production and eventually tissue damage. In this setting, targeting Treg/Th17 balance for therapeutic purposes may represent an intriguing and useful tool for SLE treatment in the next future. In this paper, the current knowledge about Treg and Th17 cells interplay in SLE will be discussed.

[1]  Jiajia Cui,et al.  Elevated Th17 cells are accompanied by FoxP3+ Treg cells decrease in patients with lupus nephritis , 2012, Rheumatology International.

[2]  C. Kallenberg,et al.  Disturbed Th1, Th2, Th17 and T(reg) balance in patients with systemic lupus erythematosus. , 2011, Clinical immunology.

[3]  G. Tsokos,et al.  Targeting lymphocyte signaling pathways as a therapeutic approach to systemic lupus erythematosus , 2011, Current opinion in rheumatology.

[4]  Ming Li,et al.  Recovery of the immune balance between Th17 and regulatory T cells as a treatment for systemic lupus erythematosus. , 2011, Rheumatology.

[5]  C. Riccardi,et al.  CD4+CD25lowGITR+ cells: A novel human CD4+ T‐cell population with regulatory activity , 2011, European journal of immunology.

[6]  C. Kallenberg,et al.  FoxP3+ CD4+ T cells in systemic autoimmune diseases: the delicate balance between true regulatory T cells and effector Th-17 cells. , 2011, Rheumatology.

[7]  D. Campbell,et al.  Phenotypical and functional specialization of FOXP3+ regulatory T cells , 2011, Nature Reviews Immunology.

[8]  JC Crispín,et al.  IL-17-producing T cells in lupus nephritis , 2011, Lupus.

[9]  J. Buckner.  Mechanisms of impaired regulation by CD4+CD25+FOXP3+ regulatory T cells in human autoimmune diseases , 2010, Nature Reviews Immunology.

[10]  R. Cervera,et al.  Systemic lupus erythematosus. , 2010, Best practice & research. Clinical rheumatology.

[11]  J. Smolen,et al.  Pathogenetic aspects of systemic lupus erythematosus with an emphasis on regulatory T cells. , 2010, Journal of autoimmunity.

[12]  D. Valmori,et al.  Human RORγt+ TH17 cells preferentially differentiate from naive FOXP3+Treg in the presence of lineage-specific polarizing factors , 2010, Proceedings of the National Academy of Sciences.

[13]  E. Jacquemin,et al.  CD25 Appears Non Essential for Human Peripheral Treg Maintenance In Vivo , 2010, PloS one.

[14]  D. Hafler,et al.  FOXP3+ regulatory T cells in the human immune system , 2010, Nature Reviews Immunology.

[15]  S. Zheng,et al.  The imbalance between regulatory and IL-17-secreting CD4+ T cells in lupus patients , 2010, Clinical Rheumatology.

[16]  I. Sanz,et al.  B cells as therapeutic targets in SLE , 2010, Nature Reviews Rheumatology.

[17]  I. Kang,et al.  Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus , 2010, Arthritis research & therapy.

[18]  S. Gaffen,et al.  Interleukin‐17 and its target genes: mechanisms of interleukin‐17 function in disease , 2010, Immunology.

[19]  Miao Yang,et al.  Plasma IL-17A Is Increased in New-Onset SLE Patients and Associated with Disease Activity , 2010, Journal of Clinical Immunology.

[20]  D. Horwitz.  Identity of mysterious CD4+CD25-Foxp3+ cells in SLE , 2010, Arthritis research & therapy.

[21]  D. Horwitz.  Identity of mysterious CD4+CD25-Foxp3+cells in systemic lupus erythematosus , 2010 .

[22]  J. Smolen,et al.  Treg and lupus , 2009, Annals of the rheumatic diseases.

[23]  Gang Wang,et al.  The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus. , 2009, Rheumatology.

[24]  Wei He,et al.  Are CD4+CD25-Foxp3+ cells in untreated new-onset lupus patients regulatory T cells? , 2009, Arthritis research & therapy.

[25]  U. Panzer,et al.  CXCR3 Mediates Renal Th1 and Th17 Immune Response in Murine Lupus Nephritis1 , 2009, The Journal of Immunology.

[26]  A. Puisieux,et al.  Interleukin 17 acts in synergy with B cell–activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus , 2009, Nature Immunology.

[27]  R. D. Hatton,et al.  Developmental plasticity of Th17 and Treg cells. , 2009, Current opinion in immunology.

[28]  E. Shevach.  Mechanisms of foxp3+ T regulatory cell-mediated suppression. , 2009, Immunity.

[29]  Ming Li,et al.  Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. , 2009, Arthritis and rheumatism.

[30]  Z. Guo,et al.  Decreased plasma IL22 levels, but not increased IL17 and IL23 levels, correlate with disease activity in patients with systemic lupus erythematosus , 2009, Annals of the rheumatic diseases.

[31]  D. Bending,et al.  Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. , 2009, The Journal of clinical investigation.

[32]  C. Riccardi,et al.  Identification of regulatory T cells in systemic lupus erythematosus. , 2009, Autoimmunity reviews.

[33]  C. Elson,et al.  Late developmental plasticity in the T helper 17 lineage. , 2009, Immunity.

[34]  Yuka Kanno,et al.  Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. , 2009, Immunity.

[35]  M. Oukka,et al.  Expanded Double Negative T Cells in Patients with Systemic Lupus Erythematosus Produce IL-17 and Infiltrate the Kidneys1 , 2008, The Journal of Immunology.

[36]  M. Ehrenstein,et al.  Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis , 2008, Proceedings of the National Academy of Sciences.

[37]  T. Yi,et al.  Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease. , 2008, Blood.

[38]  A. Ho,et al.  Reduced CD4+,CD25- T cell sensitivity to the suppressive function of CD4+,CD25high,CD127 -/low regulatory T cells in patients with active systemic lupus erythematosus. , 2008, Arthritis and rheumatism.

[39]  J. Smolen,et al.  Quantitative and qualitative deficiencies of regulatory T cells in patients with systemic lupus erythematosus (SLE). , 2008, International immunology.

[40]  C. Lam,et al.  Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. , 2008, Clinical immunology.

[41]  H. Weiner,et al.  Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor , 2008, Nature.

[42]  J. Alcocer-Varela,et al.  Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance , 2008, Lupus.

[43]  E. Wawrousek,et al.  Phenotype Switching by Inflammation-Inducing Polarized Th17 Cells, but Not by Th1 Cells1 , 2008, The Journal of Immunology.

[44]  Robert W. Williams,et al.  Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice , 2008, Nature Immunology.

[45]  P. Lipsky,et al.  Clinical significance of increased CD4+CD25−Foxp3+ T cells in patients with new-onset systemic lupus erythematosus , 2008, Annals of the rheumatic diseases.

[46]  G. de la Rosa,et al.  Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. , 2007, International immunopharmacology.

[47]  Hilde Cheroutre,et al.  Reciprocal TH17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid , 2007, Science.

[48]  Michael Liu,et al.  Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells12 , 2007, The Journal of Immunology.

[49]  A. Enk,et al.  Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus. , 2007, Arthritis and rheumatism.

[50]  P. Lipsky,et al.  Deficient CD4+CD25high T Regulatory Cell Function in Patients with Active Systemic Lupus Erythematosus1 , 2007, The Journal of Immunology.

[51]  D. Littman,et al.  The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells , 2006, Cell.

[52]  R. González-Amaro,et al.  Regulatory T cells in patients with systemic lupus erythematosus. , 2006, Journal of autoimmunity.

[53]  L. Chatenoud,et al.  Adaptive human regulatory T cells: myth or reality? , 2006, The Journal of clinical investigation.

[54]  H. Weiner,et al.  Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells , 2006, Nature.

[55]  P. Debré,et al.  Global Natural Regulatory T Cell Depletion in Active Systemic Lupus Erythematosus1 , 2005, The Journal of Immunology.

[56]  F. Silvestris,et al.  Th1 cytokines in the pathogenesis of lupus nephritis: the role of IL-18. , 2005, Autoimmunity reviews.

[57]  R. D. Hatton,et al.  Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages , 2005, Nature Immunology.

[58]  Ying Wang,et al.  A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 , 2005, Nature Immunology.

[59]  Li Li,et al.  Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 , 2003, The Journal of experimental medicine.

[60]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[61]  T. Ninomiya,et al.  Predominance of Th1 immune response in diffuse proliferative lupus nephritis. , 2001, Arthritis and rheumatism.

[62]  G. Schuler,et al.  Ex Vivo Isolation and Characterization of Cd4+Cd25+ T Cells with Regulatory Properties from Human Blood , 2001, The Journal of experimental medicine.

[63]  G. Hughes,et al.  Systemic lupus erythematosus , 2001, The Lancet.

[64]  C. Wong,et al.  Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus , 2000, Lupus.

[65]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[66]  D. Ye,et al.  Increased serum interleukin 17 in patients with systemic lupus erythematosus , 2009, Molecular Biology Reports.

[67]  David A. Isenberg,et al.  Mechanisms of Disease Systemic Lupus Erythematosus , 2008 .

[68]  A. Torgashina,et al.  Reduced number and function of CD4+CD25highFoxP3+ regulatory T cells in patients with systemic lupus erythematosus. , 2007, Advances in experimental medicine and biology.

[69]  L. Pasquier,et al.  Orphanet Journal of Rare Diseases BioMed Central Review , 2006 .

[70]  A. Andoh,et al.  Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. , 2004, Clinical immunology.