Restricted accessResearch articleFirst published online 2016-3
Circulating CD4+CD28null and extra-thymic CD4+CD8+ double positive T cells are independently associated with disease damage in systemic lupus erythematosus patients
To determine whether circulating CD4+CD28null and extra-thymic CD4+CD8+ double positive (DP) T cells are independently associated with damage accrual in systemic lupus erythematosus (SLE) patients.
Methods
This cross-sectional study was conducted between September 2013 and April 2014 in consecutive SLE patients from our Rheumatology Department. CD4+CD28null and CD4+CD8+ DP T-cell frequencies were analyzed by flow-cytometry. The association of damage (SLICC/ACR Damage Index, SDI) and CD4+CD28null and CD4+CD8+ DP T cells was examined by univariable and multivariable Poisson regression models, adjusting for possible confounders. All analyses were performed using SPSS 21.0.
Results
Patients’ (n = 133) mean (SD) age at diagnosis was 35.5 (16.8) years, 124 (93.2%) were female; all were mestizo (mixed Caucasian and Amerindian ancestry). Disease duration was 7.4 (6.8) years. The SLE Disease Activity Index was 5.5 (4.2), and the SDI 0.9 (1.2). The percentages of CD4+CD28null and CD4+CD8+ DP T cells were 17.1 (14.4) and 0.4 (1.4), respectively. The percentage of CD4+CD28null and CD4+CD8+ DP T cells were positively associated with a higher SDI in both univariable (rate ratio (RR) 1.02, 95% confidence interval (CI): 1.01–1.03 and 1.17, 95% CI: 1.07–1.27, respectively; p < 0.001 for both) and multivariable analyses RR 1.02, 95% CI: 1.01–1.03, p = 0.001 for CD4+CD28null T cells and 1.28, 95% CI: 1.13–1.44, p < 0.001 for CD4+CD8+ DP T cells). Only the renal domain remained associated with CD4+CD28null in multivariable analyses (RR 1.023 (1.002–1.045); p = 0.034).
Conclusions
In SLE patients, CD4+CD28null and CD4+CD8+ DP T cells are independently associated with disease damage. Longitudinal studies are warranted to determine the predictive value of these associations.
GhiaPPratoGStellaSScielzoCGeunaMCaligaris-CappioF. Age-dependent accumulation of monoclonal CD4+CD8+ double positive T lymphocytes in the peripheral blood of the elderly. Br J Haematol2007; 139: 780–790.
2.
WengNPAkbarANGoronzyJ. CD28(−) T cells: their role in the age-associated decline of immune function. Trends Immunol2009; 30: 306–312.
3.
NascimbeniMShinECChiribogaLKleinerDERehermannB. Peripheral CD4(+)CD8(+) T cells are differentiated effector memory cells with antiviral functions. Blood2004; 104: 478–486.
4.
MeijersRWLitjensNHde WitEA. Cytomegalovirus contributes partly to uraemia-associated premature immunological ageing of the T cell compartment. Clin Exp Immunol2013; 174: 424–432.
5.
SzczepanikMBryniarskiKTutajM. Epicutaneous immunization induces alphabeta T-cell receptor CD4 CD8 double-positive non-specific suppressor T cells that inhibit contact sensitivity via transforming growth factor-beta. Immunology2005; 115: 42–54.
6.
DasGAugustineMMDasJBottomlyKRayPRayA. An important regulatory role for CD4+CD8 alpha alpha T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease. Proc Natl Acad Sci USA2003; 100: 5324–5329.
7.
ThewissenMSomersVVenkenK. Analyses of immunosenescent markers in patients with autoimmune disease. Clin Immunol2007; 123: 209–218.
8.
QuandtDRotheKScholzRBaerwaldCWWagnerU. Peripheral CD4CD8 double positive T cells with a distinct helper cytokine profile are increased in rheumatoid arthritis. PLoS One2014; 9: e93293–e93293.
9.
LiuzzoGBiasucciLMTrottaG. Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events. J Am Coll Cardiol2007; 50: 1450–1458.
10.
BetjesMGHuismanMWeimarWLitjensNH. Expansion of cytolytic CD4+CD28- T cells in end-stage renal disease. Kidney Int2008; 74: 760–767.
11.
YadavAKJhaV. CD4+CD28null cells are expanded and exhibit a cytolytic profile in end-stage renal disease patients on peritoneal dialysis. Nephrol Dial Transplant2011; 26: 1689–1694.
12.
van LeeuwenEMRemmerswaalEBVossenMT. Emergence of a CD4+CD28- granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection. J Immunol2004; 173: 1834–1841.
13.
WeyandCMBrandesJCSchmidtDFulbrightJWGoronzyJJ. Functional properties of CD4+ CD28- T cells in the aging immune system. Mech Ageing Dev1998; 102: 131–147.
14.
LiaskouEJefferyLETrivediPJ. Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis. Gastroenterology2014; 147: 221–232 e7.
15.
MalyKSchirmerM. The story of CD4+ CD28- T cells revisited: solved or still ongoing?J Immunol Res2015; 2015: 348746–348746.
16.
ChauhanNKVajpayeeMMojumdarKSinghRSinghA. Study of CD4+CD8+ double positive T-lymphocyte phenotype and function in Indian patients infected with HIV-1. J Med Virol2012; 84: 845–856.
17.
Alonso-AriasRLopez-VazquezADiaz-PenaR. CD8dim and NKG2D expression defines related subsets of CD4+ T cells in HIV-infected patients with worse prognostic factors. J Acquir Immune Defic Syndr2009; 51: 390–398.
18.
GiraldoNABolanosNICuellarA. Increased CD4+/CD8+ double-positive T cells in chronic Chagasic patients. PLoS Negl Trop Dis2011; 5: e1294–e1294.
19.
NascimbeniMPolSSaunierB. Distinct CD4+ CD8+ double-positive T cells in the blood and liver of patients during chronic hepatitis B and C. PLoS One2011; 6: e20145–e20145.
20.
SuniMAGhanekarSAHouckDW. CD4(+)CD8(dim) T lymphocytes exhibit enhanced cytokine expression, proliferation and cytotoxic activity in response to HCMV and HIV-1 antigens. Eur J Immunol2001; 31: 2512–2520.
21.
ColombattiADolianaRSchiappacassiM. Age-related persistent clonal expansions of CD28(−) cells: phenotypic and molecular TCR analysis reveals both CD4(+) and CD4(+)CD8(+) cells with identical CDR3 sequences. Clin Immunol Immunopathol1998; 89: 61–70.
22.
PerezARMorrotABerbertLRTerra-GranadoESavinoW. Extrathymic CD4+CD8+ lymphocytes in Chagas disease: possible relationship with an immunoendocrine imbalance. Ann NY Acad Sci2012; 1262: 27–36.
23.
GordonCMatthewsNSchlesingerBC. Active systemic lupus erythematosus is associated with the recruitment of naive/resting T cells. Br J Rheumatol1996; 35: 226–230.
24.
FritschRDShenXIlleiGG. Abnormal differentiation of memory T cells in systemic lupus erythematosus. Arthritis Rheum2006; 54: 2184–2197.
25.
KochSLarbiADerhovanessianEOzcelikDNaumovaEPawelecG. Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun Ageing2008; 5: 6–6.
26.
YangDWangHNiB. Mutual activation of CD4+ T cells and monocytes mediated by NKG2D-MIC interaction requires IFN-gamma production in systemic lupus erythematosus. Mol Immunol2009; 46: 1432–1442.
27.
Mendez Castellano H, de Méndez MC. Sociedad y estratificación: método Graffar-Méndez Castellano: Fundacredesa; Caracas, Venezuela; 1994.
28.
BombardierCGladmanDDUrowitzMBCaronDChangCH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum1992; 35: 630–640.
29.
GladmanDGinzlerEGoldsmithC. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum1996; 39: 363–369.
30.
CharlsonMEPompeiPAlesKLMacKenzieCR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis1987; 40: 373–383.
31.
MakAKowNY. The pathology of T cells in systemic lupus erythematosus. J Immunol Res2014; 2014: 419029–419029.
32.
ColonnaLLoodCElkonKB. Beyond apoptosis in lupus. Curr Opin Rheumatol2014; 26: 459–466.
33.
LiuzzoGGoronzyJJYangH. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation2000; 101: 2883–2888.
GiubilatoSLiuzzoGBrugalettaS. Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus. Eur Heart J2011; 32: 1214–1226.
36.
KnudsenNHLeeCH. IL-21 and IRF4: A complex partnership in immune and metabolic regulation. Diabetes2014; 63: 1838–1840.
37.
GerliRSchillaciGGiordanoA. CD4+CD28- T lymphocytes contribute to early atherosclerotic damage in rheumatoid arthritis patients. Circulation2004; 109: 2744–2748.
38.
SunZYeHTangB. Prevalence of circulating CD4+CD28null T cells is associated with early atherosclerotic damage in patients with end-stage renal disease undergoing hemodialysis. Hum Immunol2013; 74: 6–13.
39.
YadavAKBanerjeeDLalAJhaV. Vitamin D deficiency, CD4+CD28null cells and accelerated atherosclerosis in chronic kidney disease. Nephrology (Carlton)2012; 17: 575–581.
40.
TyagiAMSrivastavaKKureelJ. Premature T cell senescence in Ovx mice is inhibited by repletion of estrogen and medicarpin: a possible mechanism for alleviating bone loss. Osteoporos Int2012; 23: 1151–1161.
41.
NiccoliGApaRLanzoneA. CD4+CD28 null T lymphocytes are expanded in young women with polycystic ovary syndrome. Fertil Steril2011; 95: 2651–2654.
42.
MoroFMorcianoATropeaA. Effects of drospirenone-ethinylestradiol and/or metformin on CD4(+)CD28(null) T lymphocytes frequency in women with hyperinsulinemia having polycystic ovary syndrome: a randomized clinical trial. Reprod Sci2013; 20: 1508–1517.
