Background: Increased numbers of TCRαβ+CD4−CD8− T cells in the peripheral blood of systemic lupus erythematosus (SLE) patients in the United States and United Kingdom have been reported. However, the proportions of TCRαβ+CD4−CD8− T cells and their involvement in the pathogenesis of SLE in Chinese populations are yet to be determined. Methods: A total of 120 SLE patients, 38 rheumatoid arthritis (RA) patients and 43 normal control subjects were examined. The proportion of TCRαβ+CD4−CD8− T cells in the peripheral blood, Fas expression on these cells, and intracellular cytokine levels in these cells were assessed using flow cytometry. Plasma cytokine concentrations were measured using enzyme-linked immunosorbent assay. Results: The percentages of TCRαβ+CD4−CD8− T cells were increased in Chinese SLE patients, particularly in active SLE patients, correlated with decreased Fas expression on these cells. IL-17 and IL-21 levels in the blood and in TCRαβ+CD4−CD8− T cells from SLE patients were increased. Moreover, a positive correlation was evident between IL-17- and IL-21-producing TCRαβ+CD4−CD8− T cells. Conclusions: Increased TCRαβ+CD4−CD8− T cells expressing inflammatory cytokines, such as IL-17 and IL-21, may be implicated in the pathogenesis of SLE in patients. Appropriate IL-17- and/or IL-21 blockage may be utilized as a novel immunotherapeutic strategy for SLE patients.
CrispinJCLiossisSNKis-TothK. Pathogenesis of human systemic lupus erythematosus: Recent advances. Trends Mol Med2010; 16: 47–57.
2.
TsokosGC. Systemic lupus erythematosus. N Engl J Med2011; 365: 2110–2121.
3.
KyttarisVC. Systemic lupus erythematosus: From genes to organ damage. Methods Mol Biol2010; 662: 265–283.
4.
MaloyKJPowrieF. Regulatory T cells in the control of immune pathology. Nat Immunol2001; 2: 816–822.
5.
ShivakumarSTsokosGCDattaSK. T cell receptor alpha/beta expressing double-negative (CD4−/CD8−) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis. J Immunol1989; 143: 103–112.
6.
D'AcquistoFCromptonT. CD3+CD4-CD8- (double negative) T cells: Saviours or villains of the immune response?Biochem Pharmacol2011; 82: 333–340.
7.
FischerKVoelklSHeymannJ. Isolation and characterization of human antigen-specific TCR alpha beta+ CD4(−) CD8-double-negative regulatory T cells. Blood2005; 105: 2828–2835.
8.
ZhangZXYangLYoungKJ. Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat Med2000; 6: 782–789.
9.
LeeBOJonesJEPetersCJ. Identification of a unique double-negative regulatory T-cell population. Immunology2011; 134: 434–447.
10.
ChenWFordMSYoungKJZhangL. The role and mechanisms of double negative regulatory T cells in the suppression of immune responses. Cell Mol Immunol2004; 1: 328–335.
11.
YeHChangYZhaoXHuangX. Characterization of CD3+CD4-CD8- (double negative) T cells reconstitution in patients following hematopoietic stem-cell transplantation. Transpl Immunol2011; 25: 180–186.
12.
VoelklSGaryRMackensenA. Characterization of the immunoregulatory function of human TCR-alphabeta(+) CD4(−) CD8(−) double-negative T cells. Eur J Immunol2011; 41: 739–748.
13.
HillhouseEEDelisleJSLesageS. Immunoregulatory CD4(−)CD8(−) T cells as a potential therapeutic tool for transplantation, autoimmunity, and cancer. Front Immunol2013; 4: 6–6.
14.
JuvetSCZhangL. Double negative regulatory T cells in transplantation and autoimmunity: Recent progress and future directions. J Mol Cell Biol2012; 4: 48–58.
15.
CrispinJCTsokosGC. Human TCR-alpha beta+ CD4- CD8- T cells can derive from CD8+ T cells and display an inflammatory effector phenotype. J Immunol2009; 183: 4675–4681.
16.
SainisKDattaSK. CD4+ T cell lines with selective patterns of autoreactivity as well as CD4- CD8- T helper cell lines augment the production of idiotypes shared by pathogenic anti-DNA autoantibodies in the NZB x SWR model of lupus nephritis. J Immunol1988; 140: 2215–2224.
17.
CrispinJCOukkaMBaylissG. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol2008; 181: 8761–8766.
18.
NagataSGolsteinP. The Fas death factor. Science1995; 267: 1449–1456.
19.
MohamoodASBargatzeDXiaoZ. Fas-mediated apoptosis regulates the composition of peripheral alphabeta T cell repertoire by constitutively purging out double negative T cells. PLoS One2008; 3: e3465–e3465.
20.
BrooksEGBalkSPAupeixK. Human T-cell receptor (TCR) alpha/beta + CD4-CD8- T cells express oligoclonal TCRs, share junctional motifs across TCR V beta-gene families, and phenotypically resemble memory T cells. Proc Natl Acad Sci U S A1993; 90: 11787–11791.
21.
Magerus-ChatinetAStolzenbergMCLoffredoMS. FAS-L, IL-10, and double-negative CD4- CD8- TCR alpha/beta+ T cells are reliable markers of autoimmune lymphoproliferative syndrome (ALPS) associated with FAS loss of function. Blood2009; 113: 3027–3030.
22.
KwanBCTamLSLaiKB. The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus. Rheumatology (Oxford)2009; 48: 1491–1497.
23.
StepanovaHMensikovaMChlebovaKFaldynaM. CD4+ and gammadelta TCR+ T lymphocytes are sources of interleukin-17 in swine. Cytokine2012; 58: 152–157.
ZhangZKyttarisVCTsokosGC. The role of IL-23/IL-17 axis in lupus nephritis. J Immunol2009; 183: 3160–3169.
26.
WongCKLitLCTamLS. Hyper production of IL-23 and IL-17 in patients with systemic lupus erythematosus: Implications for Th17-mediated inflammation in auto-immunity. Clin Immunol2008; 127: 385–393.
27.
DoreauABelotABastidJRicheBTrescol-BiemontMC. Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nat Immunol2009; 10: 778–785.
28.
YangJChuYYangX. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum2009; 60: 1472–1483.
29.
HabibTNelsonAKaushanskyK. IL-21: A novel IL-2-family lymphokine that modulates B, T, and natural killer cell responses. J Allergy Clin Immunol2003; 112: 1033–1045.
30.
SarraMMonteleoneG. Interleukin-21: A new mediator of inflammation in systemic lupus erythematosus. J Biomed Biotechnol2010; 2010: 294582–294582.
31.
LiJPanHFCenH. Interleukin-21 as a potential therapeutic target for systemic lupus erythematosus. Mol Biol Rep2011; 38: 4077–4081.
32.
DolffSAbdulahadWHWestraJ. Increase in IL-21 producing T-cells in patients with systemic lupus erythematosus. Arthritis Res Ther2011; 13: R157–R157.
33.
TanEMCohenASFriesJF. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1982; 25: 1271–1277.
34.
BombardierCGladmanDDUrowitzMB. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum1992; 35: 630–640.
35.
DeanGSAnandABlofeldA. Characterization of CD3+ CD4- CD8- (double negative) T cells in patients with systemic lupus erythematosus: production of IL-4. Lupus2002; 11: 501–507.
36.
YamadaH. Current perspectives on the role of IL-17 in autoimmune disease. J Inflamm Res2010; 3: 33–44.
37.
NalbandianACrispinJCTsokosGC. Interleukin-17 and systemic lupus erythematosus: Current concepts. Clin Exp Immunol2009; 157: 209–215.
38.
WongCKWongPTTamLS. Elevated production of B cell chemokine CXCL13 is correlated with systemic lupus erythematosus disease activity. J Clin Immunol2010; 30: 45–52.
39.
DuncanBNazarov-StoicaCSurlsJ. Double negative (CD3+ 4− 8−) TCR alphabeta splenic cells from young NOD mice provide long-lasting protection against type 1 diabetes. PLoS One2010; 5: e11427–e11427.
40.
ChenWFordMSYoungKJ. Role of double-negative regulatory T cells in long-term cardiac xenograft survival. J Immunol2003; 170: 1846–1853.
41.
CowleySCMeierovicsAIFrelingerJA. Lung CD4-CD8- double-negative T cells are prominent producers of IL-17A and IFN-gamma during primary respiratory murine infection with Francisella tularensis live vaccine strain. J Immunol2010; 184: 5791–5801.
42.
ChoYNKeeSJLeeSJ. Numerical and functional deficiencies of natural killer T cells in systemic lupus erythematosus: Their deficiency related to disease activity. Rheumatology (Oxford)2011; 50: 1054–1063.
43.
FordMSZhangZXChenWZhangL. Double-negative T regulatory cells can develop outside the thymus and do not mature from CD8+ T cell precursors. J Immunol2006; 177: 2803–2809.
44.
HaoZHampelBYagitaH. T cell-specific ablation of Fas leads to Fas ligand-mediated lymphocyte depletion and inflammatory pulmonary fibrosis. J Exp Med2004; 199: 1355–1365.
BauquetATJinHPatersonAM. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol2009; 10: 167–175.
