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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

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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.

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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

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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.

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Authors and Affiliations

  1. Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, 430022, China

    Yucheng Zhong, Xiang Wang, Xiaobo Mao, Guiwen Yi, Kai Meng, Xiaofang Yang & Qiutang Zeng

  2. Department of Cardiology, the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China

    Qingwei Ji

  3. Department of Infectious and Immunological Diseases, Medical & Health Center for Women and Children, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430016, China

    Hongxia Tang

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  1. Yucheng Zhong
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Correspondence to Qiutang Zeng.

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Yucheng Zhong, Xiang Wang, and Qingwei Ji contributed equally to this work.

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Zhong, Y., Wang, X., Ji, Q. et al. 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. J Clin Immunol 32, 1104–1117 (2012). https://doi.org/10.1007/s10875-012-9699-7

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