Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice
Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice
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DOI：
10.1172/jci31344
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发表时间：
2007-10-01
影响因子：
15.9
通讯作者：
Lichtman, Andrew H.
中科院分区：
文献类型：
--
作者：
Gotsman, Israel;Grabie, Nir;Lichtman, Andrew H.
T淋巴细胞反应促进促动脉粥样硬化性炎症事件，这是由B7家族共刺激分子的影响。B7家族负调控成员对动脉粥样硬化的影响尚未被描述。程序性死亡配体1 （Programmed death-ligand 1, PD-L1）和PD-L2是B7家族成员，在多种细胞上表达，通过与T细胞上的程序性死亡配体1 （Programmed death-1, PD-1）结合抑制T细胞活化。为了测试PD-1/PD-L通路是否调节促粥样硬化T细胞反应，我们比较了高胆固醇血症PD-L1/2(-/-)LDLR（-/-）小鼠和LDLR（-/-）对照组的动脉粥样硬化病变负荷和表型。PD-1/2缺乏导致整个主动脉动脉粥样硬化负荷显著增加，病变CD（4+）和CD(8+) T细胞数量增加。与对照组相比，PD-L1/2(-/-)LDLR（-/-）小鼠出现髂淋巴结病变，激活的CD(4+) T细胞数量增加。PD-L1/2(-/-)LDLR（-/-）小鼠血清tnf - α水平高于对照组。pd - l1 /2缺陷APCs在体外激活CD(4+) T细胞方面比对照APCs更有效，无论是否有胆固醇负荷。从高胆固醇血症PD-L1/2(-/-)LDLR（-/-）小鼠中新分离的apc比来自高胆固醇血症对照的apc刺激更大的T细胞反应。我们的研究结果表明，PD-1/PD-L通路通过限制apc依赖性T细胞的激活，在下调促粥样硬化T细胞反应和动脉粥样硬化中起重要作用。
T lymphocyte responses promote proatherogenic inflammatory events, which are influenced by costimulatory molecules of the B7 family. Effects of negative regulatory members of the B7 family on atherosclerosis have not been described. Programmed death-ligand 1 (PD-L1) and PD-L2 are B7 family members expressed on several cell types, which inhibit T cell activation via binding to programmed death-1 (PD-1) on T cells. In order to test whether the PD-1/PD-L pathway regulates proatherogenic T cell responses, we compared atherosclerotic lesion burden and phenotype in hypercholesterolemic PD-L1/2(-/-)LDLR(-/-) mice and LDLR(-/-) controls. PD-1/2 deficiency led to significantly increased atherosclerotic burden throughout the aorta and increased numbers of lesional CD(4+) and CD(8+) T cells. Compared with controls, PD-L1/2(-/-)LDLR(-/-) mice had iliac lymphadenopathy and increased numbers of activated CD(4+) T cells. Serum levels of TNF-alpha were higher in PD-L1/2(-/-)LDLR(-/-) mice than in controls. PD-L1/2-deficient APCs were more effective than control APCs in activating CD(4+) T cells in vitro, with or without cholesterol loading. Freshly isolated APCs from hypercholesterolemic PD-L1/2(-/-)LDLR(-/-) mice stimulated greater T cell responses than did APCs from hypercholesterolemic controls. Our findings indicate that the PD-1/PD-L pathway has an important role in downregulating proatherogenic T cell response and atherosclerosis by limiting APC-dependent T cell activation.