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Journal of Clinical Immunology

, Volume 32, Issue 5, pp 1104–1117 | Cite as

CD4+LAP+ and CD4+CD25+Foxp3+ Regulatory T Cells Induced by Nasal Oxidized Low-Density Lipoprotein Suppress Effector T Cells Response and Attenuate Atherosclerosis in ApoE−/− Mice

  • Yucheng Zhong
  • Xiang Wang
  • Qingwei Ji
  • Xiaobo Mao
  • Hongxia Tang
  • Guiwen Yi
  • Kai Meng
  • Xiaofang Yang
  • Qiutang Zeng
Article

Abstract

Increasing studies have demonstrated that atherosclerosis is a chronic immunoinflammatory disease, and that oxidized low-density lipoprotein (oxLDL)-specific T cells contribute to the autoimmune process in atherosclerosis. Oral administration of oxLDL, which was identified as a candidate autoantigen in atherosclerosis, was shown to induce tolerance and suppress atherogenesis. However, the precise mechanisms of mucosal tolerance induction, in particular nasal tolerance, remain unknown. In this study, we explored the effect of nasal oxLDL on atherosclerosis as well as the cellular and molecular mechanisms leading to atheroprotective responses, and then found that nasal oxLDL drastically ameliorate the initiation (47.6 %, p < 0.001) and progression (21.1 %, p = 0.001) of atherosclerosis. Most importantly, a significant 35.8 % reduction of the progression of atherosclerosis was observed in the enhanced immunization group (p < 0.001). These effects were accompanied by a significant increase in CD4+ latency-associated peptide (LAP)+ regulatory T cells (Tregs) and CD4+CD25+Foxp3+ Tregs in spleens and cervical lymph nodes, together with increased transforming growth factor (TGF)-β production and suppressed T-helper cells type 1, 2, and 17 immune responses. Surprisingly, neutralization of TGF-β in vivo partially counteracted the protective effect of nasal oxLDL treatment, indicating that the presence of TGF-β was indispensable to CD4+LAP+ Tregs and CD4+CD25+Foxp3+ Tregs to acquire regulatory properties. Our studies suggest that CD4+LAP+ Tregs and CD4+CD25+Foxp3+ Tregs induced by nasal delivery of oxLDL can inhibit oxLDL-specific T cells response and ameliorate atherosclerosis process.

Keywords

Atherosclerosis immune system regulatory T cells tolerance induction Oxidized LDL 

Abbreviations

LAP

Latency-associated peptide

ApoE

Apolipoprotein E

oxLDL

Oxidized low-density lipoprotein

Hsp

Heat stock protein

Treg

Regulatory T cell

Th1, 2, 3, and 17

T-helper type 1, 2, 3, and 17

Tr1

Regulatory T-cell type1

Foxp3

Forkhead box P3

CLN

Cervical lymph node

Teff

Effector T cell

AChR

Acetylcholine receptor

Notes

Acknowledgment

This work was supported by grant from National Natural Science Foundation of China (NO. 81070237). We thank Drs. Tony, Yanping Ding, Yidong Peng for assistance in this article.

Disclosures

The authors have no financial conflict of interest.

Supplementary material

10875_2012_9699_MOESM1_ESM.doc (78 kb)
ESM 1 (DOC 78 kb)

References

  1. 1.
    Gandhi R, Farez MF, Wang Y, Kozoriz D, Quintana FJ, Weiner HL. Cutting Edge: Human Latency-Associated Peptide+ T Cells: A Novel Regulatory T Cell Subset. J Immunol. 2010;184:4620–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Oida T, Zhang X, Goto M, Hachimura S, Totsuka M, Kaminogawa S, Weiner HL. CD4+CD25- T cells that express latency-associated peptide on the surface suppress CD4+CD45RBhigh-induced colitis by a TGF-beta-dependent mechanism. J Immunol. 2003;170:2516–22.PubMedGoogle Scholar
  3. 3.
    Sasaki N, Yamashita T, Takeda M, Shinohara M, Nakajima K, Tawa H, Usui T, Hirata K. Oral anti-CD3 antibody treatment induces regulatory T cells and inhibits the development of atherosclerosis in mice. Circulation. 2009;120:1996–2005.PubMedCrossRefGoogle Scholar
  4. 4.
    Ochi H, Abraham M, Ishikawa H, Frenkel D, Yang K, Basso AS, Wu H, Chen ML, Gandhi R, Miller A, Maron R, Weiner HL. Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25-LAP+ T cells. Nat Med. 2006;12:627–35.PubMedCrossRefGoogle Scholar
  5. 5.
    Ishikawa H, Ochi H, Chen ML, Frenkel D, Maron R, Weiner HL. Inhibition of autoimmune diabetes by oral administration of anti-CD3 monoclonal antibody. Diabetes. 2007;56:2103–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Wu HY, Center EM, Tsokos GC, Weiner HL. Suppression of murine SLE by oral anti-CD3: inducible CD4+CD25-LAP+ regulatory T cells control the expansion of IL-17+ follicular helper T cells. Lupus. 2009;18:586–96.PubMedCrossRefGoogle Scholar
  7. 7.
    Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999;340:115–26.PubMedCrossRefGoogle Scholar
  8. 8.
    Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006;6:508–19.PubMedCrossRefGoogle Scholar
  9. 9.
    Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;116:1832–44.PubMedCrossRefGoogle Scholar
  10. 10.
    Binder CJ, Chang MK, Shaw PX, Miller YI, Hartvigsen K, Dewan A, Witztum JL. Innate and acquired immunity in atherogenesis. Na Med. 2002;8:1218–26.CrossRefGoogle Scholar
  11. 11.
    Maron R, Sukhova G, Faria AM, Hoffmann E, Mach F, Libby P, Weiner HL. Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice. Circulation. 2002;106:1708–15.PubMedCrossRefGoogle Scholar
  12. 12.
    George J, Yacov N, Breitbart E, Bangio L, Shaish A, Gilburd B, Shoenfeld Y, Harats D. Suppression of early atherosclerosis in LDL-receptor deficient mice by oral tolerance with beta 2-glycoprotein I. Cardiovas Res. 2004;62:603–9.CrossRefGoogle Scholar
  13. 13.
    van Puijvelde GH, Hauer AD, de Vos P, van den Heuvel R, van Herwijnen MJ, van der Zee R, van Eden W, van Berkel TJ, Kuiper J. Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis. Circulation. 2006;114:1968–76.PubMedCrossRefGoogle Scholar
  14. 14.
    van Puijvelde GH, van Es T, van Wanrooij EJ, Habets KL, de Vos P, van der Zee R, van Eden W, van Berkel TJ, Kuiper J. Induction of oral tolerance to HSP60 or an HSP60-peptide activates T cell regulation and reduces atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27:2677–83.PubMedCrossRefGoogle Scholar
  15. 15.
    Xiong Q, Li J, Jin L, Liu J, Li T. Nasal immunization with heat shock protein 65 attenuates atherosclerosis and reduces serum lipids in cholesterol-fed wild-type rabbits probably through different mechanisms. Immunol Lett. 2009;125:40–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Tian J, Atkinson MA, Clare-Salzler M, Herschenifeld A, Forsthuber T, Lehmann PV, Kaufman DL. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J Exp Med. 1996;183:1561–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Garcia G, Komagata Y, Slavin AJ, Maron R, Weiner HL. Suppression of collagen-induced arthritis by oral or nasal administration of type-II collagen. J Autoimmun. 1999;13:315–24.PubMedCrossRefGoogle Scholar
  18. 18.
    Nussenblatt R. Orally and nasally induced tolerance studies in ocular inflammatory disease: guidance for future interventions. Ann N Y Acad Sci. 2004;1029:278–85.PubMedCrossRefGoogle Scholar
  19. 19.
    Broere F, Wieten L, Klein Koerkamp EI, van Roon JA, Guichelaar T, Lafeber FP, van Eden W. Oral or nasal antigen induces regulatory T cells that suppress arthritis and proliferation of arthritogenic T cells in joint draining lymph nodes. J Immunol. 2008;181:899–906.PubMedGoogle Scholar
  20. 20.
    Wu HY, Maron R, Tukpah AM, Weiner HL. Mucosal anti-CD3 monoclonal antibody attenuates collagen-induced arthritis that is associated with induction of LAP+ regulatory T cells and is enhanced by administration of an emulsome-based Th2-skewing adjuvant. J Immunol. 2010;185:3401–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Redgrave TG, Roberts DC, West CE. Separation of plasma lipoproteins by density-gradient ultracentrifugation. Anal Biochem. 1975;65:42–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Holven KB, Aukrust P, Holm T, Ose L, Nenseter MS. Folic acid treatment reduces chemokine release from peripheral blood mononuclear cells in hyperhomocysteinemic subjects. Arterioscler Thromb Vasc Biol. 2002;22:699–703.PubMedCrossRefGoogle Scholar
  23. 23.
    Wolvers DA, Coenen-de Roo CJ, Mebius RE, van der Cammen MJ, Tirion F, Miltenburg AM, Kraal G. Intranasal induced immunological tolerance is determined by characteristics of the draining lymph nodes: studies with OVA and human cartilage gp-39. J Immunol. 1999;162:1994–8.PubMedGoogle Scholar
  24. 24.
    Cheng X, Chen Y, Xie JJ, Yao R, Yu X, Liao MY, Ding YJ, Tang TT, Liao YH, Cheng Y. Suppressive oligodeoxynucleotides inhibit atherosclerosis in ApoE(−/−) mice through modulation of Th1/Th2 balance. J Mol Cell Cardiol. 2008;45:168–75.PubMedCrossRefGoogle Scholar
  25. 25.
    Chang MK, Binder CJ, Miller YI, Subbanagounder G, Silverman GJ, Berliner JA, Witztum JL. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory. J Exp Med. 2004;200:1359–70.PubMedCrossRefGoogle Scholar
  26. 26.
    Tang H, Zhong Y, Zhu Y, Zhao F, Cui X, Wang Z. Low responder T cell susceptibility to the suppressive function of regulatory T cells in patients with dilated cardiomyopathy. Heart. 2010;96:765–71.PubMedCrossRefGoogle Scholar
  27. 27.
    Salonen JT, Ylä-Herttuala S, Yamamoto R, Butler S, Korpela H, Salonen R, Nyyssänen K, Palinski W, Witztum JL. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet. 1992;339:883–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Ylä-Herttuala S, Palinski W, Butler SW, Picard S, Steinberg D, Witztum JL. Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL. Arterioscler Thromb. 1994;14:32–40.PubMedCrossRefGoogle Scholar
  29. 29.
    Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci USA. 1995;92:3893–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Mallat Z, Taleb S, Ait-Oufella H, Tedgui A. The role of adaptive T cell immunity in atherosclerosis. J Lipi Res. 2009;50:S364–9.CrossRefGoogle Scholar
  31. 31.
    Ma CG, Zhang GX, Xiao BG, Link J, Olsson T, Link H. Suppression of experimental autoimmune myasthenia gravis by nasal administration of acetylcholine receptor. J Neuroimmunol. 1995;58:51–60.PubMedCrossRefGoogle Scholar
  32. 32.
    Ait-Oufella H, Salomon BL, Potteaux S, Robertson AK, Gourdy P, Zoll J, Merval R, Esposito B, Cohen JL, Fisson S, Flavell RA, Hasson GK, Klatzmann D, Tedgui A, Mallat Z. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med. 2006;12:178–80.PubMedCrossRefGoogle Scholar
  33. 33.
    Ji QW, Guo M, Zheng JS, Mao XB, Peng YD, Li SN, Liang ZS, Dai ZY, Mao Y, Zeng QT. Downregulation of T helper cell type 3 in patients with acute coronary syndrome. Arch Med Res. 2009;40:285–93.PubMedCrossRefGoogle Scholar
  34. 34.
    Mallat Z, Gojova A, Brun V, Esposito B, Fournier N, Cottrez F, Tedgui A, Groux H. Induction of a regulatory T cell type 1 response reduces the development of atherosclerosis in apoE−/− mice. Circulation. 2003;108:1232–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Klingenberg R, Lebens M, Hermansson A, Fredrikson GN, Strodthoff D, Rudling M, Ketelhuth DF, Gerdes N, Holmgren J, Nilsson J, Hansson GK. Intranasal immunization with an ApoB-100 fusion protein induces antigen-specific regulatory T cells and reduces atherosclerosis. Arterioscler Thromb Vasc Biol. 2010;30:946–52.PubMedCrossRefGoogle Scholar
  36. 36.
    Chen ML, Yan BS, Bando Y, Kuchroo VK, Weiner HL. Latency-Associated Peptide Identifies a Novel CD4 + CD25 + Regulatory T Cell Subset with TGFβ-Mediated Function and Enhanced Suppression of Experimental Autoimmune Encephalomyelitis. J Immunol. 2008;180:7327–37.PubMedGoogle Scholar
  37. 37.
    Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–41.PubMedCrossRefGoogle Scholar
  38. 38.
    Robertson AK, Rudling M, Zhou X, Gorelik L, Flavell RA, Hansson GK. Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J Clin Invest. 2003;112:1342–50.PubMedGoogle Scholar
  39. 39.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med. 1996;183:2669–74.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Yucheng Zhong
    • 1
  • Xiang Wang
    • 1
  • Qingwei Ji
    • 2
  • Xiaobo Mao
    • 1
  • Hongxia Tang
    • 3
  • Guiwen Yi
    • 1
  • Kai Meng
    • 1
  • Xiaofang Yang
    • 1
  • Qiutang Zeng
    • 1
  1. 1.Laboratory of Cardiovascular Immunology, Institute of CardiologyUnion Hospital, Huazhong University of Science and TechnologyWuhanChina
  2. 2.Department of Cardiologythe People’s Hospital of Guangxi Zhuang Autonomous RegionNanningChina
  3. 3.Department of Infectious and Immunological DiseasesMedical & Health Center for Women and Children, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina

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