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
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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DOI：
10.1007/s10875-012-9699-7
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发表时间：
2012-10-01
影响因子：
9.1
通讯作者：
Zeng, Qiutang
中科院分区：
文献类型：
--
作者：
Zhong, Yucheng;Wang, Xiang;Zeng, Qiutang
越来越多的研究表明，动脉粥样硬化是一种慢性免疫炎症性疾病，氧化低密度脂蛋白（oxLDL）特异性T细胞参与动脉粥样硬化的自身免疫过程。口服oxLDL被认为是动脉粥样硬化的候选自身抗原，可诱导耐受性并抑制动脉粥样硬化的发生。然而，粘膜耐受诱导的确切机制，特别是鼻腔耐受，仍不清楚。在本研究中，我们探讨了鼻腔oxLDL对动脉粥样硬化的影响以及导致动脉粥样硬化保护反应的细胞和分子机制，发现鼻腔oxLDL可显著改善动脉粥样硬化的发生（47.6%,p < 0.001）和进展（21.1%,p = 0.001）。最重要的是，在强化免疫组中，动脉粥样硬化的进展显著减少了35.8% （p < 0.001）。这些影响伴随着脾脏和颈部淋巴结CD4（+）潜伏期相关肽（LAP）（+）调节性T细胞（Tregs）和CD4(+)CD25(+)Foxp3(+) Tregs的显著增加，转化生长因子(TGF)- β的产生增加，T辅助细胞1、2和17型免疫反应受到抑制。令人惊讶的是，体内tgf - β的中和部分抵消了鼻腔oxLDL治疗的保护作用，这表明tgf - β的存在对于CD4(+)LAP(+) Tregs和CD4(+)CD25(+)Foxp3(+) Tregs获得调节特性是必不可少的。我们的研究表明，鼻腔给药oxLDL诱导的CD4(+)LAP(+) treg和CD4(+)CD25(+)Foxp3(+) treg可以抑制oxLDL特异性T细胞反应，改善动脉粥样硬化过程。
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)-beta production and suppressed T-helper cells type 1, 2, and 17 immune responses. Surprisingly, neutralization of TGF-beta in vivo partially counteracted the protective effect of nasal oxLDL treatment, indicating that the presence of TGF-beta 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.