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


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.


Atherosclerosis immune system regulatory T cells tolerance induction Oxidized LDL 



Latency-associated peptide


Apolipoprotein E


Oxidized low-density lipoprotein


Heat stock protein


Regulatory T cell

Th1, 2, 3, and 17

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


Regulatory T-cell type1


Forkhead box P3


Cervical lymph node


Effector T cell


Acetylcholine receptor



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.


The authors have no financial conflict of interest.

Supplementary material

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


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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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