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Plasma phospholipid transfer protein (PLTP) modulates adaptive immune functions through alternation of T helper cell polarization

Abstract

Objective: Plasma phospholipid transfer protein (PLTP) is a key determinant of lipoprotein metabolism, and both animal and human studies converge to indicate that PLTP promotes atherogenesis and its thromboembolic complications. Moreover, it has recently been reported that PLTP modulates inflammation and immune responses. Although earlier studies from our group demonstrated that PLTP can modify macrophage activation, the implication of PLTP in the modulation of T-cell-mediated immune responses has never been investigated and was therefore addressed in the present study. Approach and results: In the present study, we demonstrated that PLTP deficiency in mice has a profound effect on CD4+ Th0 cell polarization, with a shift towards the anti-inflammatory Th2 phenotype under both normal and pathological conditions. In a model of contact hypersensitivity, a significantly impaired response to skin sensitization with the hapten-2,4-dinitrofluorobenzene (DNFB) was observed in PLTP-deficient mice compared to wild-type (WT) mice. Interestingly, PLTP deficiency in mice exerted no effect on the counts of total white blood cells, lymphocytes, granulocytes, or monocytes in the peripheral blood. Moreover, PLTP deficiency did not modify the amounts of CD4+ and CD8+ T lymphocyte subsets. However, PLTP-deficiency, associated with upregulation of the Th2 phenotype, was accompanied by a significant decrease in the production of the pro-Th1 cytokine interleukin 18 by accessory cells. Conclusions: For the first time, this work reports a physiological role for PLTP in the polarization of CD4+ T cells toward the pro-inflammatory Th1 phenotype.

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References

  1. Bingle CD, Craven CJ . Meet the relatives: a family of BPI- and LBP-related proteins. Trends Immunol 2004; 25: 53–55.

    Article  CAS  PubMed  Google Scholar 

  2. Albers JJ, Vuletic S, Cheung MC . Role of plasma phospholipid transfer protein in lipid and lipoprotein metabolism. Biochim Biophys Acta 2012; 1821: 345–357.

    Article  CAS  PubMed  Google Scholar 

  3. Jiang X-C, Jin W, Hussain MM . The impact of phospholipid transfer protein (PLTP) on lipoprotein metabolism. Nutr Metab (Lond) 2012; 9: 75.

    Article  CAS  Google Scholar 

  4. Jiang XC, Qin S, Qiao C, Kawano K, Lin M, Skold A et al. Apolipoprotein B secretion and atherosclerosis are decreased in mice with phospholipid-transfer protein deficiency. Nat Med 2001; 7: 847–852.

    Article  CAS  PubMed  Google Scholar 

  5. Jiang X-C, Li Z, Liu R, Yang XP, Pan M, Lagrost L et al. Phospholipid transfer protein deficiency impairs apolipoprotein-B secretion from hepatocytes by stimulating a proteolytic pathway through a relative deficiency of vitamin E and an increase in intracellular oxidants. J Biol Chem 2005; 280: 18336–18340.

    Article  CAS  PubMed  Google Scholar 

  6. Yazdanyar A, Quan W, Jiang X-C . Liver-specific phospholipid transfer protein deficiency reduces high-density lipoprotein and non-high-density lipoprotein production in mice. Arterioscler Thromb Vasc Biol 2013; 33: 2058–2064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jiang X-C, Tall AR, Qin S, Lin M, Schneider M, Lalanne F et al. Phospholipid transfer protein deficiency protects circulating lipoproteins from oxidation due to the enhanced accumulation of vitamin E. J Biol Chem 2002; 277: 31850–31856.

    Article  CAS  PubMed  Google Scholar 

  8. Desrumaux C, Deckert V, Lemaire-Ewing S, Mossiat C, Athias A, Vandroux D et al. Plasma phospholipid transfer protein deficiency in mice is associated with a reduced thrombotic response to acute intravascular oxidative stress. Arterioscler Thromb Vasc Biol 2010; 30: 2452–2457.

    Article  CAS  PubMed  Google Scholar 

  9. Tzotzas T, Desrumaux C, Lagrost L . Plasma phospholipid transfer protein (PLTP): review of an emerging cardiometabolic risk factor. Obes Rev 2009; 10: 403–411.

    Article  CAS  PubMed  Google Scholar 

  10. Yan D, Navab M, Bruce C, Fogelman AM, Jiang X-C . PLTP deficiency improves the anti-inflammatory properties of HDL and reduces the ability of LDL to induce monocyte chemotactic activity. J Lipid Res 2004; 45: 1852–1858.

    Article  CAS  PubMed  Google Scholar 

  11. Cheung MC, Vaisar T, Han X, Heinecke JW, Albers JJ . Phospholipid transfer protein in human plasma associates with proteins linked to immunity and inflammation. Biochemistry (Mosc) 2010; 49: 7314–7322.

    Article  CAS  Google Scholar 

  12. Cheung MC, Brown BG, Marino Larsen EK, Frutkin AD, O’Brien KD, Albers JJ . Phospholipid transfer protein activity is associated with inflammatory markers in patients with cardiovascular disease. Biochim Biophys Acta 2006; 1762: 131–137.

    Article  CAS  PubMed  Google Scholar 

  13. Tan KCB, Shiu SWM, Wong Y, Tam S . Plasma phospholipid transfer protein activity and subclinical inflammation in type 2 diabetes mellitus. Atherosclerosis 2005; 178: 365–370.

    Article  CAS  PubMed  Google Scholar 

  14. Papoutsidakis N, Deftereos S, Giannopoulos G, Panagopoulou V, Manolis AS, Bouras G . Treating Dyslipidemias: Is Inflammation the Missing Link? Med Chem 2014; 10: 643–652.

    Article  CAS  PubMed  Google Scholar 

  15. Witztum JL, Lichtman AH . The influence of innate and adaptive immune responses on atherosclerosis. Annu Rev Pathol 2014; 9: 73–102.

    Article  CAS  PubMed  Google Scholar 

  16. Golia E, Limongelli G, Natale F, Fimiani F, Maddaloni V, Pariggiano I et al. Inflammation and cardiovascular disease: from pathogenesis to therapeutic target. Curr Atheroscler Rep 2014; 16: 435.

    Article  PubMed  Google Scholar 

  17. Tse K, Tse H, Sidney J, Sette A, Ley K . T cells in atherosclerosis. Int Immunol 2013; 25: 615–622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ait-Oufella H, Sage AP, Mallat Z, Tedgui A . Adaptive (T and B cells) immunity and control by dendritic cells in atherosclerosis. Circ Res 2014; 114: 1640–1660.

    Article  CAS  PubMed  Google Scholar 

  19. Ogier N, Klein A, Deckert V, Athias A, Bessède G, Le Guern N et al. Cholesterol accumulation is increased in macrophages of phospholipid transfer protein-deficient mice: normalization by dietary alpha-tocopherol supplementation. Arterioscler Thromb Vasc Biol 2007; 27: 2407–2412.

    Article  CAS  PubMed  Google Scholar 

  20. Vikstedt R, Metso J, Hakala J, Olkkonen VM, Ehnholm C, Jauhiainen M . Cholesterol efflux from macrophage foam cells is enhanced by active phospholipid transfer protein through generation of two types of acceptor particles. Biochemistry 2007; 46: 11979–11986.

    Article  CAS  PubMed  Google Scholar 

  21. Annunziato F, Romagnani S . Heterogeneity of human effector CD4+ T cells. Arthritis Res Ther 2009; 11: 257.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Schlitt A, Liu J, Yan D, Mondragon-Escorpizo M, Norin AJ, Jiang X-C . Anti-inflammatory effects of phospholipid transfer protein (PLTP) deficiency in mice. Biochim Biophys Acta 2005; 1733: 187–191.

    Article  CAS  PubMed  Google Scholar 

  23. Shelly L, Royer L, Sand T, Jensen H, Luo Y . Phospholipid transfer protein deficiency ameliorates diet-induced hypercholesterolemia and inflammation in mice. J Lipid Res 2008; 49: 773–781.

    Article  CAS  PubMed  Google Scholar 

  24. Deckert V, Kretz B, Habbout A, Raghay K, Labbé J, Abello N et al. Development of abdominal aortic aneurysm is decreased in mice with plasma phospholipid transfer protein deficiency. Am J Pathol 2013; 183: 975–986.

    Article  CAS  PubMed  Google Scholar 

  25. Barlage S, Fröhlich D, Böttcher A, Jauhiainen M, Müller HP, Noetzel F et al. ApoE-containing high density lipoproteins and phospholipid transfer protein activity increase in patients with a systemic inflammatory response. J Lipid Res 2001; 42: 281–290.

    CAS  PubMed  Google Scholar 

  26. Watford WT, Moriguchi M, Morinobu A, O’Shea JJ . The biology of IL-12: coordinating innate and adaptive immune responses. Cytokine Growth Factor Rev 2003; 14: 361–368.

    Article  CAS  PubMed  Google Scholar 

  27. Swain SL . Interleukin 18: tipping the balance toward a T helper cell 1 response. J Exp Med 2001; 194: F11–F14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H . Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev 2001; 12: 53–72.

    Article  CAS  PubMed  Google Scholar 

  29. Masson D, Deckert V, Gautier T, Klein A, Desrumaux C, Viglietta C et al. Worsening of diet-induced atherosclerosis in a new model of transgenic rabbit expressing the human plasma phospholipid transfer protein. Arterioscler Thromb Vasc Biol 2011; 31: 766–774.

    Article  CAS  PubMed  Google Scholar 

  30. Libby P, Lichtman AH, Hansson GK . Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity 2013; 38: 1092–1104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Frostegård J, Ulfgren AK, Nyberg P, Hedin U, Swedenborg J, Andersson U et al. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 1999; 145: 33–43.

    Article  PubMed  Google Scholar 

  32. Taleb S, Tedgui A, Mallat Z . Adaptive T cell immune responses and atherogenesis. Curr Opin Pharmacol 2010; 10: 197–202.

    Article  CAS  PubMed  Google Scholar 

  33. Whitman SC, Ravisankar P, Daugherty A . Interleukin-18 enhances atherosclerosis in apolipoprotein E(−/−) mice through release of interferon-gamma. Circ Res 2002; 90: E34–E38.

    Article  CAS  PubMed  Google Scholar 

  34. De Nooijer R, von der Thüsen JH, Verkleij CJN, Kuiper J, Jukema JW, van der Wall EE et al. Overexpression of IL-18 decreases intimal collagen content and promotes a vulnerable plaque phenotype in apolipoprotein-E-deficient mice. Arterioscler Thromb Vasc Biol 2004; 24: 2313–2319.

    Article  CAS  PubMed  Google Scholar 

  35. Elhage R, Jawien J, Rudling M, Ljunggren H-G, Takeda K, Akira S et al. Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. Cardiovasc Res 2003 59: 234–240.

    Article  CAS  PubMed  Google Scholar 

  36. Mallat Z, Corbaz A, Scoazec A, Graber P, Alouani S, Esposito B et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res 2001; 89: E41–E45.

    CAS  PubMed  Google Scholar 

  37. Gerdes N, Sukhova GK, Libby P, Reynolds RS, Young JL, Schönbeck U . Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med 2002; 195: 245–257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mallat Z, Corbaz A, Scoazec A, Besnard S, Lesèche G, Chvatchko Y et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation 2001; 104: 1598–1603.

    Article  CAS  PubMed  Google Scholar 

  39. Mallat Z, Henry P, Fressonnet R, Alouani S, Scoazec A, Beaufils P et al. Increased plasma concentrations of interleukin-18 in acute coronary syndromes. Heart 2002; 88: 467–469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kawasaki D, Tsujino T, Morimoto S, Fujioka Y, Naito Y, Okumura T et al. Usefulness of circulating interleukin-18 concentration in acute myocardial infarction as a risk factor for late restenosis after emergency coronary angioplasty. Am J Cardiol 2003 91: 1258–1261.

    Article  CAS  PubMed  Google Scholar 

  41. Naito Y, Tsujino T, Fujioka Y, Ohyanagi M, Okamura H, Iwasaki T . Increased circulating interleukin-18 in patients with congestive heart failure. Heart 2002; 88: 296–297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yamaoka-Tojo M, Tojo T, Wakaume K, Kameda R, Nemoto S, Takahira N et al. Circulating interleukin-18: a specific biomarker for atherosclerosis-prone patients with metabolic syndrome. Nutr Metab (Lond) 2011; 8: 3.

    Article  CAS  Google Scholar 

  43. Seta Y, Kanda T, Tanaka T, Arai M, Sekiguchi K, Yokoyama T et al. Interleukin 18 in acute myocardial infarction. Heart 2000; 84: 668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Blankenberg S, Luc G, Ducimetière P, Arveiler D, Ferrières J, Amouyel P et al. Interleukin-18 and the risk of coronary heart disease in European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation 2003; 108: 2453–2459.

    Article  CAS  PubMed  Google Scholar 

  45. Saggini A, Anogeianaki A, Maccauro G, Teté S, Salini V, Caraffa A et al. Cholesterol, cytokines and diseases. Int J Immunopathol Pharmacol 2011; 24: 567–581.

    Article  CAS  PubMed  Google Scholar 

  46. Izsepi E, Himer L, Szilagyi O, Hadju P, Panyi G, Laszlo G et al. Membrane microdomain organization, calcium signal, and NFAT activation as an important axis in polarized Th cell function. Cytometry A 2013; 83: 185–196.

    Article  PubMed  Google Scholar 

  47. Newton AH, Benedict SH . Low density lipoprotein promotes human naive T cell differentiation to Th1 cells. Hum Immunol 2014; 75: 621–628.

    Article  CAS  PubMed  Google Scholar 

  48. Chauveau A, Le Floc’h A, Bantilan NS, Koretzky GA, Huse M . Diacylglycerol kinase α establishes T cell polarity by shaping diacylglycerol accumulation at the immunological synapse. Sci Signal 2014; 7: ra82.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Desrumaux C, Deckert V, Athias A, Masson D, Lizard G, Palleau V et al. Plasma phospholipid transfer protein prevents vascular endothelium dysfunction by delivering alpha-tocopherol to endothelial cells. FASEB J 1999; 13: 883–892.

    Article  CAS  PubMed  Google Scholar 

  50. Desrumaux C, Risold P-Y, Schroeder H, Deckert V, Masson D, Athias A et al. Phospholipid transfer protein (PLTP) deficiency reduces brain vitamin E content and increases anxiety in mice. FASEB J 2005; 19: 296–297.

    Article  CAS  PubMed  Google Scholar 

  51. Drouineaud V, Lagrost L, Klein A, Desrumaux C, Le Guern N, Athias A et al. Phospholipid transfer protein deficiency reduces sperm motility and impairs fertility of mouse males. FASEB J 2006; 20: 794–796.

    Article  CAS  PubMed  Google Scholar 

  52. Pekmezci D . Vitamin E and immunity. Vitam Horm 2011; 86: 179–215.

    Article  CAS  PubMed  Google Scholar 

  53. Meydani SN, Han SN, Wu D . Vitamin E and immune response in the aged: molecular mechanisms and clinical implications. Immunol Rev 2005; 205: 269–284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Adolfsson O, Huber BT, Meydani SN . Vitamin E-enhanced IL-2 production in old mice: naive but not memory T cells show increased cell division cycling and IL-2-producing capacity. J Immunol 2001; 167: 3809–3817.

    Article  CAS  PubMed  Google Scholar 

  55. Klein A, Deckert V, Schneider M, Dutrillaux F, Hammann A, Athias A et al. Alpha-tocopherol modulates phosphatidylserine externalization in erythrocytes: relevance in phospholipid transfer protein-deficient mice. Arterioscler Thromb Vasc Biol 2006; 26: 2160–2167.

    Article  CAS  PubMed  Google Scholar 

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We thank Philip Bastable for editing this article.

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Correspondence to Catherine Desrumaux.

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Desrumaux, C., Lemaire-Ewing, S., Ogier, N. et al. Plasma phospholipid transfer protein (PLTP) modulates adaptive immune functions through alternation of T helper cell polarization. Cell Mol Immunol 13, 795–804 (2016). https://doi.org/10.1038/cmi.2015.75

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