T-cell abnormalities and aberrant T helper cytokine profiles have been implicated in the loss of immune tolerance to nuclear and cytoplasmic antigens and linked to a variety of clinical manifestations in systemic lupus erythematosus (SLE). Here, we review the role of T cells in promoting and maintaining SLE in relation to their cellular and molecular abnormalities and provide an update on recent T cell-targeted therapeutic approaches for the restoration of T cell homeostasis in the disease.
1 Arbuckle MR McClain MT Rubertone MV . Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med2003; 349: 1526–1533.
2.
2 Datta SK Patel H Berry D . Induction of a cationic shift in IgG anti-DNA autoantibodies. Role of T helper cells with classical and novel phenotypes in three murine models of lupus nephritis. J Exp Med1987; 165: 1252–1268.
3.
3 Santoro TJ Portanova JP Kotzin BL . The contribution of L3T4+ T cells to lymphoproliferation and autoantibody production in MRLlpr/lpr mice. J Exp Med1988; 167: 1713–1718.
4.
4 Singh RR Dubey S . Autoantigens and defects in immune tolerance in lupus. In: DJ Wallace BH Hahn , (eds), Dubois’ Lupus Erythematosus.7th ed.Philadelphia: Lippincott William & Wilkins; 2007. p. 370–406.
5.
5 Wofsy D Seaman WE . Reversal of advanced murine lupus in NZB/NZW F1 mice by treatment with monoclonal antibody to L3T4. J Immunol1987; 138: 3247–3253.
6.
6 Mihara M Ohsugi Y Saito K . Immunologic abnormality in NZB/NZW F1 mice. Thymus-independent occurrence of B cell abnormality and requirement for T cells in the development of autoimmune disease, as evidenced by an analysis of the athymic nude individuals. J Immunol1988; 141: 85–90.
7.
7 Messner RP Lindström FD Williams RC . Peripheral blood lymphocyte cell surface markers during the course of systemic lupus erythematosus. J Clin Invest1973; 52: 3046–3056.
8.
8 Glinski W Gershwin ME Steinberg AD . Fractionation of cells on a discontinuous Ficoll gradient. Study of subpopulations of human T cells using anti-T-cell antibodies from patients with systemic lupus erythematosus. J Clin Invest1976; 57: 604–614.
9.
9 Rivero SJ Llorente L Díaz-Jouanen E Alarcón-Segovia D . T-lymphocyte subpopulation in untreated SLE. Variations with disease activity. Arthritis Rheum1977; 20: 1169–1173.
10.
10 Rivero SJ Díaz-Jouanen E Alarcón-Segovia D . Lymphopenia in systemic lupus erythematosus. Clinical, diagnostic, and prognostic significance. Arthritis Rheum1978; 21: 295–305.
11.
11 Bakke AC Kirkland PA Kitridou RC . T lymphocyte subsets in systemic lupus erythematosus. Correlations with corticosteroid therapy and disease activity. Arthritis Rheum1983; 26: 745–750.
12.
12 Wither J Vukusic B . Autoimmunity develops in lupus-prone NZB mice despite normal T cell tolerance. J Immunol1998; 161: 4555–4562.
13.
13 Fatenejad S Peng SL Disorbo O Craft J . Central T cell tolerance in lupus-prone mice: influence of autoimmune background and the lpr mutation. J Immunol1998; 161: 6427–6432.
14.
14 Xu L Zhang L Yi Y Kang HK Datta SK . Human lupus T cells resist inactivation and escape death by upregulating COX-2. Nat Med2004; 10: 411–415.
15.
15 Budagyan VM Bulanova EG Sharova NI Nikonova MF Stanislav ML Yarylin AA . The resistance of activated T-cells from SLE patients to apoptosis induced by human thymic stromal cells. Immunol Lett1998; 60: 1–5.
16.
16 Horwitz DA Gray JD . The interaction of T cells with cells of the innate immune system and B cells in the pathogenesis of SLE. In: DJ Wallace BH Hahn , (eds), Dubois’ lupus erythematosus.6th ed.Philadelphia: Lippincott William & Wilkins; 2002 p. 133–160.
17.
17 La Cava A . T-regulatory cells in systemic lupus erythematosus. Lupus2008; 17: 421–425.
18.
18 Murashima A Takasaki Y Ohgaki M Hashimoto H Shirai T Hirose S . Activated peripheral blood mononuclear cells detected by murine monoclonal antibodies to proliferating cell nuclear antigen in active lupus patients. J Clin Immunol1990; 10: 28–37.
19.
19 Dawisha SM Gmelig-Meyling F Steinberg AD . Assessment of clinical parameters associated with increased frequency of mutant T cells in patients with systemic lupus erythematosus. Arthritis Rheum1994; 37: 270–277.
20.
20 Campen DH Horwitz DA Quismorio FP Ehresmann GR Martin WJ . Serum levels of interleukin-2 receptor and activity of rheumatic diseases characterized by immune system activation. Arthritis Rheum1988; 31: 1358–1364.
21.
21 Samsonov MY Tilz GP Egorova O . Serum soluble markers of immune activation and disease activity in systemic lupus erythematosus. Lupus1995; 4: 29–32.
22.
22 Aderka D Wysenbeek A Engelmann H . Correlation between serum levels of soluble tumor necrosis factor receptor and disease activity in systemic lupus erythematosus. Arthritis Rheum1993; 36: 1111–1120.
23.
23 Okudaira K Searles RP Goodwin JS Williams RC . Antibodies in the sera of patients with systemic lupus erythematosus that block the binding of monoclonal anti-Ia to Ia-positive targets also inhibit the autologous mixed lymphocyte response. J Immunol1982; 129: 582–586.
24.
24 Yamada A Shaw M Winfield JB . Surface antigen specificity of cold-reactive IgM antilymphocyte antibodies in systemic lupus erythematosus. Arthritis Rheum1985; 28: 44–51.
25.
25 Wernet P Kunkel HG . Antibodies to a specific surface antigen of T cells in human sera inhibiting mixed leukocyte culture reactions. J Exp Med1973; 138: 1021–1026.
26.
26 Hahn BH Pletscher LS Muniain M MacDermott RP . Suppression of the normal autologous mixed leukocyte reaction by sera from patients with systemic lupus erythematosus. Arthritis Rheum1982; 25: 381–389.
27.
27 Charpentier B Carnaud C Bach JF . Selective depression of the xenogeneic cell-mediated lympholysis in systemic lupus erythematosus. J Clin Invest1979; 64: 351–360.
28.
28 Raziuddin S Nur MA Al-Wabel AA . Increased circulating HLA-DR+ CD4+ T cells in systemic lupus erythematosus: alterations associated with prednisolone therapy. Scand J Immunol1990; 31: 139–145.
29.
29 Vassilopoulos D Kovacs B Tsokos GC . TCR/CD3 complex-mediated signal transduction pathway in T cells and T cell lines from patients with systemic lupus erythematosus. J Immunol1995; 155: 2269–2281.
30.
30 Blasini AM Alonzo E Chacón R Riera R Stekman IL Rodriguez MA . Abnormal pattern of tyrosine phosphorylation in unstimulated peripheral blood T lymphocytes from patients with systemic lupus erythematosus. Lupus1998; 7: 515–523.
31.
31 Kammer GM Laxminarayana D Khan IU . Mechanisms of deficient type I protein kinase a activity in lupus T lymphocytes. Int Rev Immunol2004; 23: 225–244.
32.
32 Takeuchi T Pang M Amano K Koide J Abe T . Reduced protein tyrosine phosphatase (PTPase) activity of CD45 on peripheral blood lymphocytes in patients with systemic lupus erythematosus (SLE). Clin Exp Immunol1997; 109: 20–26.
33.
33 Jury EC Kabouridis PS Abba A Mageed RA Isenberg DA . Increased ubiquitination and reduced expression of LCK in T lymphocytes from patients with systemic lupus erythematosus. Arthritis Rheum2003; 48: 1343–1354.
34.
34 Yi Y McNerney M Datta SK . Regulatory defects in Cbl and mitogen-activated protein kinase (extracellular signal-related kinase) pathways cause persistent hyperexpression of CD40 ligand in human lupus T cells. J Immunol2000; 165: 6627–6634.
35.
35 Tenbrock K Juang YT Tolnay M Tsokos GC . The cyclic adenosine 5′-monophosphate response element modulator suppresses IL-2 production in stimulated T cells by a chromatin-dependent mechanism. J Immunol2003; 170: 2971–2976.
36.
36 Sierakowski S Kucharz EJ Lightfoot RW Goodwin JS . Impaired T-cell activation in patients with systemic lupus erythematosus. J Clin Immunol1989; 9: 469–476.
37.
37 Perl A Nagy G Gergely P Puskas F Qian Y Banki K . Apoptosis and mitochondrial dysfunction in lymphocytes of patients with systemic lupus erythematosus. Methods Mol Med2004; 102: 87–114.
38.
38 Juang YT Wang Y Solomou EE . Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV. J Clin Invest2005; 115: 996–1005.
39.
39 Dauphinée MJ Kipper SB Wofsy D Talal N . Interleukin 2 deficiency is a common feature of autoimmune mice. J Immunol1981; 127: 2483–2487.
40.
40 Altman A Theofilopoulos AN Weiner R Katz DH Dixon FJ . Analysis of T cell function in autoimmune murine strains. Defects in production and responsiveness to interleukin 2. J Exp Med1981; 154: 791–808.
41.
41 Wofsy D Murphy ED Roths JB Dauphinée MJ Kipper SB Talal N . Deficient interleukin 2 activity in MRL/Mp and C57BL/6J mice bearing the lpr gene. J Exp Med1981; 154: 1671–1680.
42.
42 Alcocer-Varela J Alarcón-Segovia D . Decreased production of and response to interleukin-2 by cultured lymphocytes from patients with systemic lupus erythematosus. J Clin Invest1982; 69: 1388–1392.
43.
43 Linker-Israeli M Bakke AC Kitridou RC Gendler S Gillis S Horwitz DA . Defective production of interleukin 1 and interleukin 2 in patients with systemic lupus erythematosus (SLE). J Immunol1983; 130: 2651–2655.
44.
44 Tsokos GC Nambiar MP Tenbrock K Juang YT . Rewiring the T-cell: signaling defects and novel prospects for the treatment of SLE. Trends Immunol2003; 24: 259–263.
45.
45 Cedeño S Cifarelli DF Blasini AM . Defective activity of ERK-1 and ERK-2 mitogen-activated protein kinases in peripheral blood T lymphocytes from patients with systemic lupus erythematosus: potential role of altered coupling of Ras guanine nucleotide exchange factor hSos to adapter protein Grb2 in lupus T cells. Clin Immunol2003; 106: 41–49.
46.
46 Katsiari CG Kyttaris VC Juang YT Tsokos GC . Protein phosphatase 2A is a negative regulator of IL-2 production in patients with systemic lupus erythematosus. J Clin Invest2005; 115: 3193–3204.
47.
47 Jury EC Kabouridis PS . T-lymphocyte signalling in systemic lupus erythematosus: a lipid raft perspective. Lupus2004; 13: 413–422.
48.
48 Krishnan S Nambiar MP Warke VG . Alterations in lipid raft composition and dynamics contribute to abnormal T cell responses in systemic lupus erythematosus. J Immunol2004; 172: 7821–7831.
49.
49 Jury EC Kabouridis PS Abba A Mageed RA Isenberg DA . Increased ubiquitination and reduced expression of LCK in T lymphocytes from patients with systemic lupus erythematosus. Arthritis Rheum2003; 48: 1343–1354.
50.
50 Jury EC Kabouridis PS Flores-Borja F Mageed RA Isenberg DA . Altered lipid raft-associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus. J Clin Invest2004; 113: 1176–1187.
51.
51 Mishra N Reilly CM Brown DR Ruiz P Gilkeson GS . Histone deacetylase inhibitors modulate renal disease in the MRLlpr/lpr mouse. J Clin Invest2003; 111: 539–552.
52.
52 Singh RP Hahn BH La Cava A . Tuning immune suppression in systemic autoimmunity with self-derived peptides. (http://www.ncbi.nlm.nih.gov/pubmed/19075790?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum). Inflamm Allergy Drug Targets2008; 7: 253–259.
53.
53 Mauermann N Sthoeger Z Zinger H Mozes E . Amelioration of lupus manifestations by a peptide based on the complementarity determining region 1 of an autoantibody in severe combined immunodeficient (SCID) mice engrafted with peripheral blood lymphocytes of systemic lupus erythematosus (SLE) patients. Clin Exp Immunol2004; 137: 513–520.
54.
54 Luger D Dayan M Zinger H Liu J Mozes E . A peptide based on the complementarity determining region 1 of a human monoclonal autoantibody ameliorates spontaneous and induced lupus manifestations in correlation with cytokine immunomodulation. J Clin Immunol2004; 24: 579–590.
55.
55 Ramanujam M Wang X Huang W . Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus. J Immunol2004; 173: 3524–3534.
56.
56 Ferrera F; Filaci G; Rizzi M; . New therapies in SLE. Recents Patents Inflamm Allergy Drug Discov 2008; 2: 11–23.
57.
57 Mohan C Shi Y Laman J Datta S . Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol1995; 154: 1470–1480.
58.
58 Koshy M Berger D Crow M . Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J Clin Invest1996; 98: 826–837.
59.
59 Yellin M D'Agati V Parkinson G . Immunohistologic analysis of renal CD40 and CD40L expression in lupus nephritis and other glomerulonephritides. Arthritis Rheum1997; 40: 124–134.
60.
60 Wang X Huang W Schiffer L . Effects of anti-CD154 treatment on B cells in murine systemic lupus erythematosus. Arthritis Rheum2003; 48: 495–506.
61.
61 Huang W Sinha J Newman J . The effect of anti-CD40 ligand antibody on B cells in human systemic lupus erythematosus. Arthritis Rheum2002; 46: 1554–1562.
62.
62 Davis JJ Totoritis M Rosenberg J Sklenar T Wofsy D . Phase I clinical trial of a monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus. J Rheumatol2001; 28: 95–101.
63.
63 Kalunian K Davis JJ Merrill J Totoritis M Wofsy D . Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum2002; 46: 3251–3258.
64.
64 Boumpas D Furie R Manzi S . A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum2003; 48: 719–727.
65.
65 McAdam A Greenwald R Levin M . ICOS is critical for CD40-mediated antibody class switching. Nature2001; 409: 102–105.
66.
66 Iwai H Abe M Hirose S . Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis. J Immunol2003; 171: 2848–2854.
67.
67 Sun Y Subudhi S Fu Y . Co-stimulation agonists as a new immunotherapy for autoimmune diseases. Trends Mol Med2003; 9: 483–489.
68.
68 Sun Y Chen H Subudhi S . Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat Med2002; 8: 1405–1413.
69.
69 Mittler R Foell J McCausland M . Anti-CD137 antibodies in the treatment of autoimmune disease and cancer. Immunol Res2004; 29: 197–208.
