TAP1-Deficiency Does Not Alter Atherosclerosis Development in Apoe−/− Mice

Antigen presenting cells (APC) have the ability to present both extra-cellular and intra-cellular antigens via MHC class I molecules to CD8+ T cells. The cross presentation of extra-cellular antigens is reduced in mice with deficient Antigen Peptide Transporter 1 (TAP1)-dependent MHC class I antigen presentation, and these mice are characterized by a diminished CD8+ T cell population. We have recently reported an increased activation of CD8+ T cells in hypercholesterolemic Apoe−/− mice. Therefore, this study included TAP1-deficient Apoe−/− mice (Apoe−/−Tap1−/−) to test the atherogenicity of CD8+ T cells and TAP1-dependent cross presentation in a hypercholesterolemic environment. As expected the CD8+ T cell numbers were low in Apoe−/−Tap1−/− mice in comparison to Apoe−/− mice, constituting ∼1% of the lymphocyte population. In spite of this there were no differences in the extent of atherosclerosis as assessed by en face Oil Red O staining of the aorta and cross-sections of the aortic root between Apoe−/−Tap1−/− and Apoe−/− mice. Moreover, no differences were detected in lesion infiltration of macrophages or CD3+ T cells in Apoe−/−Tap1−/− compared to Apoe−/− mice. The CD3+CD4+ T cell fraction was increased in Apoe−/−Tap1−/− mice, suggesting a compensation for the decreased CD8+ T cell population. Interestingly, the fraction of CD8+ effector memory T cells was increased but this appeared to have little impact on the atherosclerosis development. In conclusion, Apoe−/−Tap1−/− mice develop atherosclerosis equal to Apoe−/− mice, indicating a minor role for CD8+ T cells and TAP1-dependent antigen presentation in the disease process.抗原呈递细胞（Antigen presenting cells, APC）可通过主要组织相容性复合体I类分子（Major Histocompatibility Complex class I, MHC I）向CD8阳性T细胞（CD8+ T cells）呈递细胞外与细胞内抗原。依赖抗原肽转运蛋白1（Antigen Peptide Transporter 1, TAP1）的MHC I类抗原呈递通路缺陷的小鼠，其细胞外抗原交叉呈递能力受损，且该类小鼠的CD8阳性T细胞群体数量显著减少。我们近期的研究报道，高胆固醇血症载脂蛋白E敲除（Apoe−/−）小鼠体内CD8阳性T细胞的活化水平升高。因此，本研究构建抗原肽转运蛋白1缺陷的载脂蛋白E敲除（Apoe−/−Tap1−/−）小鼠模型，旨在探究高胆固醇血症环境下CD8阳性T细胞的致动脉粥样硬化性，以及依赖TAP1的抗原交叉呈递在该过程中的作用。正如预期，与Apoe−/−小鼠相比，Apoe−/−Tap1−/−小鼠的CD8阳性T细胞数量极低，仅占淋巴细胞群体的约1%。尽管如此，通过主动脉铺片油红O染色及主动脉根横切片评估的动脉粥样硬化病变程度，在Apoe−/−Tap1−/−与Apoe−/−小鼠之间未见显著差异。此外，相较于Apoe−/−小鼠，Apoe−/−Tap1−/−小鼠的动脉粥样硬化病灶内巨噬细胞及CD3阳性T细胞（CD3+ T cells）浸润程度亦无明显差异。Apoe−/−Tap1−/−小鼠体内CD3阳性CD4阳性T细胞（CD3+CD4+ T cells）比例升高，提示其对CD8阳性T细胞数量减少存在代偿机制。值得注意的是，尽管Apoe−/−Tap1−/−小鼠的CD8阳性效应记忆T细胞（CD8+ effector memory T cells）比例有所升高，但这似乎对动脉粥样硬化的发生发展几乎无影响。综上，Apoe−/−Tap1−/−小鼠的动脉粥样硬化病变程度与Apoe−/−小鼠相当，表明CD8阳性T细胞及依赖TAP1的抗原呈递过程在该疾病进程中仅发挥微弱作用。