Background The lipid milleu exacerbates the inflammatory response in atherosclerosis but its effect on T cell mediated immune response has not been fully elucidated. We hypothesized that lipid lowering would modulate T cell mediated immune function. Methods and Results T cells isolated from human PBMC or splenic T cells from apoE-/- mouse had higher proliferative response to T cell receptor (TCR) ligation in medium supplemented with 10% fetal bovine serum (FBS) compared to medium with 10% delipidated FBS. The differences in proliferation were associated with changes in lipid rafts, cellular cholesterol content, IL-10 secretion and subsequent activation of signaling molecule activated by TCR ligation. Immune biomarkers were also assessed in vivo using male apoE-/- mice fed atherogenic diet (AD) starting at 7 weeks of age. At 25 weeks of age, a sub-group was switched to normal diet (ND) whereas the rest remained on AD until euthanasia at 29 weeks of age. Dietary change resulted in a lower circulating level of cholesterol, reduced plaque size and inflammatory phenotype of plaques. These changes were associated with reduced intracellular IL-10 and IL-12 expression in CD4+ and CD8+ T cells. Conclusion Our results show that lipid lowering reduces T cell proliferation and function, supporting the notion that lipid lowering modulates T cell function in vivo and in vitro.
References
[1]
Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, et al. (2001) Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 103: 926–933. doi: 10.1161/01.cir.103.7.926
[2]
Cipollone F, Fazia M, Iezzi A, Zucchelli M, Pini B, et al. (2003) Suppression of the functionally coupled cyclooxygenase-2/prostaglandin E synthase as a basis of simvastatin-dependent plaque stabilization in humans. Circulation 107: 1479–1485. doi: 10.1161/01.cir.0000056530.03783.81
[3]
Zhao XQ, Yuan C, Hatsukami TS, Frechette EH, Kang XJ, et al. (2001) Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI: a case-control study. Arterioscler Thromb Vasc Biol 21: 1623–1629. doi: 10.1161/hq1001.098463
[4]
Aikawa M, Rabkin E, Voglic SJ, Shing H, Nagai R, et al. (1998) Lipid lowering promotes accumulation of mature smooth muscle cells expressing smooth muscle myosin heavy chain isoforms in rabbit atheroma. Circ Res 83: 1015–1026. doi: 10.1161/01.res.83.10.1015
[5]
Aikawa M, Voglic SJ, Sugiyama S, Rabkin E, Taubman MB, et al. (1999) Dietary lipid lowering reduces tissue factor expression in rabbit atheroma. Circulation 100: 1215–1222. doi: 10.1161/01.cir.100.11.1215
[6]
Farmer JA (2000) Pleiotropic effects of statins. Curr Atheroscler Rep 2: 208–217. doi: 10.1007/s11883-000-0022-3
[7]
Gotto JA Jr, Farmer JA (2001) Pleiotropic effects of statins: do they matter? Curr Opin Lipidol 12: 391–394. doi: 10.1097/00041433-200108000-00004
[8]
Mays ME, Dujovne CA (2008) Pleiotropic effects: should statins be considered an essential component in the treatment of dyslipidemia? Curr Atheroscler Rep 10: 45–52. doi: 10.1007/s11883-008-0008-0
[9]
Pasterkamp G, van Lammeren GW (2010) Pleiotropic effects of statins in atherosclerotic disease. Expert Rev Cardiovasc Ther 8: 1235–1237. doi: 10.1586/erc.10.107
[10]
Wilhelm AJ, Zabalawi M, Grayson JM, Weant AE, Major AS, et al. (2009) Apolipoprotein A-I and its role in lymphocyte cholesterol homeostasis and autoimmunity. Arterioscler Thromb Vasc Biol 29: 843–849. doi: 10.1161/atvbaha.108.183442
[11]
Armstrong AJ, Gebre AK, Parks JS, Hedrick CC (2010) ATP-binding cassette transporter G1 negatively regulates thymocyte and peripheral lymphocyte proliferation. J Immunol 184: 173–183. doi: 10.4049/jimmunol.0902372
[12]
Zhou X, Paulsson G, Stemme S, Hansson GK (1998) Hypercholesterolemia is associated with a T helper (Th) 1/Th2 switch of the autoimmune response in atherosclerotic apo E-knockout mice. J Clin Invest 101: 1717–1725. doi: 10.1172/jci1216
[13]
Zhou X, Johnston TP, Johansson D, Parini P, Funa K, et al. (2009) Hypercholesterolemia leads to elevated TGF-beta1 activity and T helper 3-dependent autoimmune responses in atherosclerotic mice. Atherosclerosis 204: 381–387. doi: 10.1016/j.atherosclerosis.2008.10.017
[14]
Robertson AK, Zhou X, Strandvik B, Hansson GK (2004) Severe hypercholesterolaemia leads to strong Th2 responses to an exogenous antigen. Scand J Immunol 59: 285–293. doi: 10.1111/j.0300-9475.2004.01403.x
[15]
Graham LS, Tintut Y, Parhami F, Kitchen CM, Ivanov Y, et al. (2010) Bone density and hyperlipidemia: the T-lymphocyte connection. J Bone Miner Res 25: 2460–2469. doi: 10.1002/jbmr.148
[16]
Chyu KY, Reyes OS, Zhao X, Yano J, Dimayuga P, et al. (2004) Timing affects the efficacy of LDL immunization on atherosclerotic lesions in apo E (-/-) mice. Atherosclerosis 176: 27–35. doi: 10.1016/j.atherosclerosis.2004.04.016
[17]
Muller CP, Stephany DA, Winkler DF, Hoeg JM, Demosky SJ Jr, et al. (1984) Filipin as a flow microfluorometry probe for cellular cholesterol. Cytometry 5: 42–54. doi: 10.1002/cyto.990050108
[18]
Surls J, Nazarov-Stoica C, Kehl M, Olsen C, Casares S, et al. (2012) Increased membrane cholesterol in lymphocytes diverts T-cells toward an inflammatory response. PLoS ONE 7: e38733. doi: 10.1371/journal.pone.0038733
[19]
Fulop TJ, Douziech N, Goulet AC, Desgeorges S, Linteau A, et al. (2001) Cyclodextrin modulation of T lymphocyte signal transduction with aging. Mech Ageing Dev 122: 1413–1430. doi: 10.1016/s0047-6374(01)00274-3
[20]
Nix M, Stoffel W (2000) Perturbation of membrane microdomains reduces mitogenic signaling and increases susceptibility to apoptosis after T cell receptor stimulation. Cell Death Differ 7: 413–424. doi: 10.1038/sj.cdd.4400666
[21]
Guy CS, Vignali KM, Temirov J, Bettini ML, Overacre AE, et al. (2013) Distinct TCR signaling pathways drive proliferation and cytokine production in T cells. Nat Immunol 14: 262–270. doi: 10.1038/ni.2538
[22]
Cuthbert JA, Lipsky PE (1986) Promotion of human T lymphocyte activation and proliferation by fatty acids in low density and high density lipoproteins. J Biol Chem 261: 3620–3627.
[23]
Cuthbert JA, Lipsky PE (1984) Modulation of human lymphocyte responses by low density lipoproteins (LDL): enhancement but not immunosuppression is mediated by LDL receptors. Proc Natl Acad Sci U S A 81: 4539–4543. doi: 10.1073/pnas.81.14.4539
[24]
Cuthbert JA, Lipsky PE (1987) Provision of cholesterol to lymphocytes by high density and low density lipoproteins. Requirement for low density lipoprotein receptors. J Biol Chem 262: 7808–7818.
[25]
Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, et al. (2008) LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134: 97–111. doi: 10.1016/j.cell.2008.04.052
[26]
Maganto-Garcia E, Tarrio ML, Grabie N, Bu DX, Lichtman AH (2011) Dynamic changes in regulatory T cells are linked to levels of diet-induced hypercholesterolemia. Circulation 124: 185–195. doi: 10.1161/circulationaha.110.006411
[27]
Ornish D, Brown SE, Scherwitz LW, Billings JH, Armstrong WT, et al. (1990) Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet 336: 129–133. doi: 10.1016/0140-6736(90)91656-u
[28]
Watts GF, Lewis B, Brunt JN, Lewis ES, Coltart DJ, et al. (1992) Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas' Atherosclerosis Regression Study (STARS). Lancet 339: 563–569. doi: 10.1016/0140-6736(92)90863-x
[29]
Caruzzo C, Liboni W, Bonzano A, Bobbio M, Bongioanni S, et al. (1995) Effect of lipid-lowering treatment on progression of atherosclerotic lesions—a duplex ultrasonographic investigation. Angiology 46: 269–280. doi: 10.1177/000331979504600401
[30]
Aikawa M, Rabkin E, Okada Y, Voglic SJ, Clinton SK, et al. (1998) Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization. Circulation 97: 2433–2444. doi: 10.1161/01.cir.97.24.2433
