Agonistic Anti-TIGIT Treatment Inhibits T Cell Responses in LDLr Deficient Mice without Affecting Atherosclerotic Lesion Development
Agonistic Anti-TIGIT Treatment Inhibits T Cell Responses in LDLr Deficient Mice without Affecting Atherosclerotic Lesion Development
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DOI：
10.1371/journal.pone.0083134
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发表时间：
2013-12-20
期刊：
影响因子：
3.7
通讯作者：
van Puijvelde, Gijs H. M.
中科院分区：
文献类型：
--
作者：
Foks, Amanda C.;Ran, Ingrid A.;van Puijvelde, Gijs H. M.
目的：共刺激和共抑制分子主要表达在T细胞和抗原提呈细胞上，强烈协调适应性免疫反应。虽然共刺激分子增强免疫反应，但通过共抑制分子传递信号会抑制免疫系统，从而显示出预防心血管疾病的巨大治疗潜力。通过共抑制T细胞免疫球蛋白和ITIM结构域(TIGIT)的信号传递直接抑制T细胞的激活和增殖，因此是一种新的候选治疗方法，可以特异性地抑制促动脉粥样硬化的T细胞的反应性。在本研究中，我们使用一种激动型抗TIGIT抗体来确定过度的TIGIT信号在动脉粥样硬化中的作用。方法和结果：与喂食食物的小鼠相比，TIGIT上调了饲喂西式饲料的小鼠的CD4(+)T细胞。激动型抗TIGIT在体外和体内均能抑制T细胞的激活和增殖。然而，与PBS和亚美尼亚仓鼠免疫球蛋白治疗相比，喂食西式饮食4或8周的LDLR-/-小鼠的激动型抗TIGIT治疗并未影响动脉粥样硬化病变的发展。此外，在激动型抗TIGIT治疗的小鼠的血液和脾中观察到树突状细胞的百分比增加。此外，这些细胞的活化状态增加，但IL-10的产生减少。结论：尽管脾T细胞反应受到抑制，激动型抗TIGIT治疗并不影响动脉粥样硬化的初始发展，可能是由于树突状细胞的活性增加所致。
Objective: Co-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 Results:TIGIT 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.Conclusions: Despite 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.