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

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.