Abstract
Natural CD4+CD25+ regulatory T cells (Treg) show a potent immunosuppressive function and contribute to immunologic self-tolerance by suppressing potentially auto-reactive T cells. Depletion of these cells leads to the induction of severe autoimmune diseases in animal models; more recently, several studies have also reported an impairment of Treg number and/or function in various human autoimmune diseases. For example, aberrant numbers of circulating CD4+CD25+ Treg have been seen in patients with type I diabetes, mycosis fungoides, graft-versus-host-reaction, and rheumatoid arthritis. Moreover, increased numbers of functionally active CD4+CD25+ Treg have been detected in the synovial fluid of patients with rheumatoid arthritis. In systemic lupus erythematosus (SLE), conflicting data on the role of CD4+CD25+ Treg in human autoimmune diseases have been presented in the literature. Decreased numbers of peripheral blood Treg have been reported by most studies on SLE patients with active disease, but non-impaired or even increased CD4+CD25+ Treg numbers have also been described. In addition, both deficient and normal suppressive capacity of isolated Treg have been observed in SLE. Analysis of CD4+FoxP3+ Treg in skin lesions of patients with a primarily cutaneous manifestation of the disease showed a significant reduction in cell numbers as compared to other inflammatory skin diseases, suggesting the importance of analyzing Treg numbers in the affected tissue. In this review, we discuss the role of CD4+CD25+ Treg in autoimmunity and recent published data on SLE. Furthermore, we highlight the need for additional studies that address specific gaps of knowledge regarding the pathophysiological mechanisms as well as the identification of future therapeutic strategies for autoimmune diseases.
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Abbreviations
- APC:
-
Antigen-presenting cells
- CLE:
-
Cutaneous lupus erythematosus
- IFN-γ:
-
Interferon gamma
- IL:
-
Interleukin
- RA:
-
Rheumatoid arthritis
- SLE:
-
Systemic lupus erythematosus
- Tconv :
-
Conventional T cells
- Treg :
-
Regulatory T cells
- TCR:
-
T cell receptor
- TGF-β:
-
Transforming growth factor beta
References
Alvarado-Sanchez B, Hernandez-Castro B, Portales-Perez D et al (2006) Regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 27:110–118. doi:10.1016/j.jaut.2006.06.005
Azab NA, Bassyouni IH, Emad Y et al (2008) CD4+CD25+ regulatory T cells (TREG) in systemic lupus erythematosus (SLE) patients: the possible influence of treatment with corticosteroids. Clin Immunol 127:151–157. doi:10.1016/j.clim.2007.12.010
Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA (2001) CD4+CD25 high regulatory cells in human peripheral blood. J Immunol 167:1245–1253
Barath S, Aleksza M, Tarr T et al (2007) Measurement of natural (CD4+CD25 high) and inducible (CD4+IL−10+) regulatory T cells in patients with systemic lupus erythematosus. Lupus 16:489–496. doi:10.1177/0961203307080226
Barath S, Soltesz P, Kiss E et al (2007) The severity of systemic lupus erythematosus negatively correlates with the increasing number of CD4+CD25(high)FoxP3+regulatory T cells during repeated plasmapheresis treatments of patients. Autoimmunity 40:521–528. doi:10.1080/08916930701610028
Beissert S, Schwarz A, Schwarz T (2006) Regulatory T cells. J Invest Dermatol 126:15–24. doi:10.1038/sj.jid.5700004
Bennett CL, Christie J, Ramsdell F et al (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20–21. doi:10.1038/83713
Berger CL, Tigelaar R, Cohen J et al (2005) Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells. Blood 105:1640–1647. doi:10.1182/blood-2004-06-2181
Bohm M, Luger TA, Schneider M, Schwarz T, Kuhn A (2006) New insight into immunosuppression and treatment of autoimmune diseases. Clin Exp Rheumatol 24:S67–S71
Bonelli M, Savitskaya A, von Dalwigk K et al (2008) Quantitative and qualitative deficiencies of regulatory T cells in patients with systemic lupus erythematosus (SLE). Int Immunol 20:861–868. doi:10.1093/intimm/dxn044
Boyer O, Saadoun D, Abriol J et al (2004) CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis. Blood 103:3428–3430. doi:10.1182/blood-2003-07-2598
Brunkow ME, Jeffery EW, Hjerrild KA et al (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27:68–73. doi:10.1038/83784
Cao D, Borjesson O, Larsson P et al (2006) FOXP3 identifies regulatory CD25bright CD4+T cells in rheumatic joints. Scand J Immunol 63:444–452. doi:10.1111/j.1365-3083.2006.001755.x
Cao D, Malmstrom V, Baecher-Allan C et al (2003) Isolation and functional characterization of regulatory CD25brightCD4+T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol 33:215–223. doi:10.1002/immu.200390024
Cao D, van Vollenhoven R, Klareskog L, Trollmo C, Malmstrom V (2004) CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res Ther 6:R335–R346. doi:10.1186/ar1192
Cepika AM, Marinic I, Morovic-Vergles J, Soldo-Juresa D, Gagro A (2007) Effect of steroids on the frequency of regulatory T cells and expression of FOXP3 in a patient with systemic lupus erythematosus: a two-year follow-up. Lupus 16:374–377. doi:10.1177/0961203307077990
Chatila TA (2005) Role of regulatory T cells in human diseases. J Allergy Clin Immunol 116:949–959. quiz 960. doi:10.1016/j.jaci.2005.08.047
Cohen JL, Boyer O (2006) The role of CD4+CD25 high regulatory T cells in the physiopathogeny of graft-versus-host disease. Curr Opin Immunol 18:580–585. doi:10.1016/j.coi.2006.07.007
Cools N, Ponsaerts P, Van Tendeloo VF, Berneman ZN (2007) Regulatory T cells and human disease. Clin Dev Immunol 2007:89195. doi:10.1155/2007/89195
Costantino CM, Baecher-Allan CM, Hafler DA (2008) Human regulatory T cells and autoimmunity. Eur J Immunol 38:921–924. doi:10.1002/eji.200738104
Crispin JC, Martinez A, Alcocer-Varela J (2003) Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 21:273–276. doi:10.1016/S0896-8411(03)00121-5
Dejaco C, Duftner C, Grubeck-Loebenstein B, Schirmer M (2006) Imbalance of regulatory T cells in human autoimmune diseases. Immunology 117:289–300. doi:10.1111/j.1365-2567.2005.02317.x
Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G (2001) Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med 193:1303–1310. doi:10.1084/jem.193.11.1303
Fathy A, Mohamed RW, Tawfik GA, Omar AS (2005) Diminished CD4+CD25+ T-lymphocytes in peripheral blood of patients with systemic lupus erythematosus. Egypt J Immunol 12:25–31
Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336. doi:10.1038/ni904
Franz B, Fritzsching B, Riehl A et al (2007) Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus. Arthritis Rheum 56:1910–1920. doi:10.1002/art.22699
Gondek DC, Lu LF, Quezada SA, Sakaguchi S, Noelle RJ (2005) Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol 174:1783–1786
Haas J, Hug A, Viehover A et al (2005) Reduced suppressive effect of CD4+CD25 high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur J Immunol 35:3343–3352. doi:10.1002/eji.200526065
Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061. doi:10.1126/science.1079490
Jonuleit H, Schmitt E, Stassen M et al (2001) Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 193:1285–1294. doi:10.1084/jem.193.11.1285
Khattri R, Cox T, Yasayko SA, Ramsdell F (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4:337–342. doi:10.1038/ni909
Klemke CD, Fritzsching B, Franz B et al (2006) Paucity of FOXP3+ cells in skin and peripheral blood distinguishes Sezary syndrome from other cutaneous T-cell lymphomas. Leukemia 20:1123–1129. doi:10.1038/sj.leu.2404182
Kriegel MA, Lohmann T, Gabler C et al (2004) Defective suppressor function of human CD4+CD25+ regulatory T cells in autoimmune polyglandular syndrome type II. J Exp Med 199:1285–1291. doi:10.1084/jem.20032158
Kuhn A, Bijl M (2008) Pathogenesis of cutaneous lupus erythematosus. Lupus 17:389–393. doi:10.1177/0961203308090019
Kukreja A, Cost G, Marker J et al (2002) Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest 109:131–140
Lee HY, Hong YK, Yun HJ et al (2008) Altered frequency and migration capacity of CD4+CD25+ regulatory T cells in systemic lupus erythematosus. Rheumatol (Oxf) 47:789–794. doi:10.1093/rheumatology/ken108
Lee JH, Wang LC, Lin YT et al (2006) Inverse correlation between CD4+ regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus. Immunology 117:280–286. doi:10.1111/j.1365-2567.2005.02306.x
Lim HW, Hillsamer P, Banham AH, Kim CH (2005) Cutting edge: direct suppression of B cells by CD4+CD25+ regulatory T cells. J Immunol 175:4180–4183
Lin SC, Chen KH, Lin CH et al (2007) The quantitative analysis of peripheral blood FOXP3-expressing T cells in systemic lupus erythematosus and rheumatoid arthritis patients. Eur J Clin Invest 37:987–996. doi:10.1111/j.1365-2362.2007.01882.x
Lindley S, Dayan CM, Bishop A et al (2005) Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 54:92–99. doi:10.2337/diabetes.54.1.92
Loser K, Beissert S (2007) Dendritic cells and T cells in the regulation of cutaneous immunity. Adv Dermatol 23:307–333. doi:10.1016/j.yadr.2007.07.014
Loser K, Scherer A, Krummen MB et al (2005) An important role of CD80/CD86-CTLA-4 signaling during photocarcinogenesis in mice. J Immunol 174:5298–5305
Lyssuk EY, Torgashina AV, Soloviev SK, Nassonov EL, Bykovskaia SN (2007) Reduced number and function of CD4+CD25 highFoxP3+ regulatory T cells in patients with systemic lupus erythematosus. Adv Exp Med Biol 601:113–119
Mellor-Pita S, Citores MJ, Castejon R et al (2006) Decrease of regulatory T cells in patients with systemic lupus erythematosus. Ann Rheum Dis 65:553–554. doi:10.1136/ard.2005.044974
Miyara M, Amoura Z, Parizot C et al (2005) Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol 175:8392–8400
Miyara M, Amoura Z, Parizot C et al (2006) The immune paradox of sarcoidosis and regulatory T cells. J Exp Med 203:359–370. doi:10.1084/jem.20050648
Monk CR, Spachidou M, Rovis F et al (2005) MRL/Mp CD4+, CD25-T cells show reduced sensitivity to suppression by CD4+, CD25+ regulatory T cells in vitro: a novel defect of T cell regulation in systemic lupus erythematosus. Arthritis Rheum 52:1180–1184. doi:10.1002/art.20976
Ou LS, Goleva E, Hall C, Leung DY (2004) T regulatory cells in atopic dermatitis and subversion of their activity by superantigens. J Allergy Clin Immunol 113:756–763. doi:10.1016/j.jaci.2004.01.772
Piccirillo CA, Shevach EM (2001) Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J Immunol 167:1137–1140
Sakaguchi S (2003) Regulatory T cells: mediating compromises between host and parasite. Nat Immunol 4:10–11. doi:10.1038/ni0103-10
Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562. doi:10.1146/annurev.immunol.21.120601.141122
Sakaguchi S (2008) Regulatory T cells in the past and for the future. Eur J Immunol 38:901–937. doi:10.1002/eji.200890012
Sakaguchi S, Sakaguchi N (2005) Regulatory T cells in immunologic self-tolerance and autoimmune disease. Int Rev Immunol 24:211–226. doi:10.1080/08830180590934976
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) 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. J Immunol 155:1151–1164
Sakaguchi S, Sakaguchi N, Shimizu J et al (2001) Immunologic tolerance maintained by CD25+CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182:18–32. doi:10.1034/j.1600-065X.2001.1820102.x
Sfikakis PP, Souliotis VL, Fragiadaki KG et al (2007) Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis. Clin Immunol 123:66–73. doi:10.1016/j.clim.2006.12.006
Shevach EM (2000) Regulatory T cells in autoimmmunity. Annu Rev Immunol 18:423–449. doi:10.1146/annurev.immunol.18.1.423
Shevach EM (2002) CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389–400
Smyth MJ, Teng MW, Swann J et al (2006) CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J Immunol 176:1582–1587
Suarez A, Lopez P, Gomez J, Gutierrez C (2006) Enrichment of CD4+CD25 high T cell population in patients with systemic lupus erythematosus treated with glucocorticoids. Ann Rheum Dis 65:1512–1517. doi:10.1136/ard.2005.049924
Sugiyama H, Gyulai R, Toichi E et al (2005) Dysfunctional blood and target tissue CD4+CD25 high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 174:164–173
Thornton AM, Donovan EE, Piccirillo CA, Shevach EM (2004) Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol 172:6519–6523
Thornton AM, Shevach EM (1998) CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188:287–296. doi:10.1084/jem.188.2.287
Thornton AM, Shevach EM (2000) Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 164:183–190
Trzonkowski P, Szmit E, Mysliwska J, Dobyszuk A, Mysliwski A (2004) CD4+CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction. Clin Immunol 112:258–267. doi:10.1016/j.clim.2004.04.003
Valencia X, Stephens G, Goldbach-Mansky R et al (2006) TNF downmodulates the function of human CD4+CD25high T-regulatory cells. Blood 108:253–261. doi:10.1182/blood-2005-11-4567
Valencia X, Yarboro C, Illei G, Lipsky PE (2007) Deficient CD4+CD25 high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol 178:2579–2588
Vallerskog T, Gunnarsson I, Widhe M et al (2007) Treatment with rituximab affects both the cellular and the humoral arm of the immune system in patients with SLE. Clin Immunol 122:62–74. doi:10.1016/j.clim.2006.08.016
Vargas-Rojas MI, Crispin JC, Richaud-Patin Y, Alcocer-Varela J (2008) Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance. Lupus 17:289–294. doi:10.1177/0961203307088307
Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA (2004) Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 199:971–979. doi:10.1084/jem.20031579
Wang HY, Lee DA, Peng G et al (2004) Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity 20:107–118. doi:10.1016/S1074-7613(03)00359-5
Wildin RS, Ramsdell F, Peake J et al (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27:18–20. doi:10.1038/83707
Wing K, Ekmark A, Karlsson H, Rudin A, Suri-Payer E (2002) Characterization of human CD25+CD4+ T cells in thymus, cord and adult blood. Immunology 106:190–199. doi:10.1046/j.1365-2567.2002.01412.x
Wu HY, Staines NA (2004) A deficiency of CD4+CD25+ T cells permits the development of spontaneous lupus-like disease in mice, and can be reversed by induction of mucosal tolerance to histone peptide autoantigen. Lupus 13:192–200. doi:10.1191/0961203303lu1002oa
Yan B, Ye S, Chen G et al (2008) Dysfunctional CD4+, CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells. Arthritis Rheum 58:801–812. doi:10.1002/art.23268
Zhang B, Zhang X, Tang F, Zhu L, Liu Y (2008) Reduction of forkhead box P3 levels in CD4(+)CD25(high) T cells in patients with new-onset systemic lupus erythematosus. Clin Exp Immunol 153:182–187
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This work was supported by a grant from the German Research Foundation (DFG) to A. K. (KU 1559/1-2) and S.B. (SFB 293 B8).
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Kuhn, A., Beissert, S. & Krammer, P.H. CD4+CD25+ regulatory T cells in human lupus erythematosus. Arch Dermatol Res 301, 71–81 (2009). https://doi.org/10.1007/s00403-008-0891-9
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DOI: https://doi.org/10.1007/s00403-008-0891-9