Agonistic Anti-TIGIT Treatment Inhibits T Cell Responses in LDLr Deficient Mice without Affecting Atherosclerotic Lesion Development

ObjectiveCo-stimulatory and co-inhibitory molecules are mainly expressed on T cells and antigen presenting cells and strongly orchestrate adaptive immune responses. Whereas co-stimulatory molecules enhance immune responses, signaling via co-inhibitory molecules dampens the immune system, thereby showing great therapeutic potential to prevent cardiovascular diseases. Signaling via co-inhibitory T cell immunoglobulin and ITIM domain (TIGIT) directly inhibits T cell activation and proliferation, and therefore represents a novel therapeutic candidate to specifically dampen pro-atherogenic T cell reactivity. In the present study, we used an agonistic anti-TIGIT antibody to determine the effect of excessive TIGIT-signaling on atherosclerosis.Methods and ResultsTIGIT was upregulated on CD4+ T cells isolated from mice fed a Western-type diet in comparison with mice fed a chow diet. Agonistic anti-TIGIT suppressed T cell activation and proliferation both in vitro and in vivo. However, agonistic anti-TIGIT treatment of LDLr−/− mice fed a Western-type diet for 4 or 8 weeks did not affect atherosclerotic lesion development in comparison with PBS and Armenian Hamster IgG treatment. Furthermore, elevated percentages of dendritic cells were observed in the blood and spleen of agonistic anti-TIGIT-treated mice. Additionally, these cells showed an increased activation status but decreased IL-10 production.ConclusionsDespite the inhibition of splenic T cell responses, agonistic anti-TIGIT treatment does not affect initial atherosclerosis development, possibly due to increased activity of dendritic cells.共刺激分子与共抑制分子主要表达于T细胞与抗原呈递细胞（antigen-presenting cells），可强力调控适应性免疫应答。共刺激分子可增强免疫应答，而共抑制分子介导的信号通路则会抑制免疫系统，因此在预防心血管疾病领域展现出巨大的治疗潜力。共抑制分子T细胞免疫球蛋白和ITIM结构域（T cell immunoglobulin and ITIM domain, TIGIT）介导的信号通路可直接抑制T细胞活化与增殖，因此是特异性抑制致动脉粥样硬化性T细胞反应的新型治疗候选靶点。本研究采用激动型抗TIGIT抗体，探究过度激活TIGIT信号通路对动脉粥样硬化的影响。方法与结果：与喂食普通饲料的小鼠相比，喂食西式饲料的小鼠分离得到的CD4+ T细胞中TIGIT表达水平上调。激动型抗TIGIT抗体在体外与体内实验中均可抑制T细胞活化与增殖。然而，对喂食西式饲料的低密度脂蛋白受体敲除（LDLr−/−）小鼠分别进行4周或8周的激动型抗TIGIT抗体治疗，与磷酸盐缓冲液（phosphate-buffered saline, PBS）对照组及亚美尼亚仓鼠IgG对照组相比，其动脉粥样硬化斑块的形成未受明显影响。此外，接受激动型抗TIGIT抗体治疗的小鼠血液与脾脏中，树突状细胞的比例升高；且此类树突状细胞的活化状态增强，但IL-10的产生量降低。结论：尽管激动型抗TIGIT抗体治疗可抑制脾脏T细胞应答，但该治疗并不会影响动脉粥样硬化的初始发生发展，这一现象可能与树突状细胞活性增强有关。