Flego Davide, Severino Anna, Trotta Francesco, Previtero Marco, Ucci Sara, Zara Chiara, Pedicino Daniela, Massaro Gianluca, Biasucci Luigi M, Liuzzo Giovanna, Crea Filippo
Institute of Cardiology, Catholic University, Largo A. Gemelli, 8, 00168, Rome, Italy.
Basic Res Cardiol. 2014;109(6):448. doi: 10.1007/s00395-014-0448-3. Epub 2014 Oct 26.
In acute coronary syndrome (ACS), T cell abnormalities are associated to a worse outcome. Loss of inhibitory activity of CD31, an Ig-like adhesion molecule, on peripheral leukocytes has been found to enhance atherosclerosis in experimental models. In this study, we examined the expression of CD31 on T cells, and its role on TCR signaling in 35 patients with non-ST elevation ACS, in 35 patients with stable angina (SA), and in 35 controls. Furthermore, 10 ACS and 10 SA patients were re-analyzed at 1-year follow-up. Flow-cytometry analysis showed that in ACS patients, CD31 expression was reduced on total CD4(+) and CD4(+)CD28(null) (P < 0.001, ACS vs. SA), on naïve (P < 0.001, ACS vs. SA) and on central-memory and effector-memory CD4(+) T cells (P < 0.05, ACS vs. SA and controls). The immunomodulatory effect of CD31 on TCR signaling of CD4(+) and CD4(+)CD28(null) T cells, was lower in ACS than SA patients (P < 0.05, for both comparisons). At 1-year follow-up, CD31 expression and function increased in ACS becoming similar to that found in SA. CD31 recruitment in the immunological synapse was lower in ACS than controls (P = 0.012). Moreover, CD31 modulated MAPK signaling and reduced the expression of T bet and Rorγ-t, necessary for Th1 and Th17 differentiation. Finally, we studied TCR signaling in CD31(+) naïve and primed T cell subsets observing a different pattern of protein phosphorylation. A CD31-mediated regulatory pathway is enhanced in SA and temporarily downregulated in ACS. As CD31 modulates both T cell activation, by increasing the threshold for TCR stimulation, and T cell differentiation, it might represent a novel molecular target to treat T cell abnormalities in ACS.
在急性冠状动脉综合征（ACS）中，T细胞异常与更差的预后相关。在实验模型中，已发现免疫球蛋白样粘附分子CD31对外周白细胞抑制活性的丧失会加重动脉粥样硬化。在本研究中，我们检测了35例非ST段抬高型ACS患者、35例稳定型心绞痛（SA）患者和35例对照者T细胞上CD31的表达及其对TCR信号传导的作用。此外，对10例ACS患者和10例SA患者进行了1年随访后的重新分析。流式细胞术分析显示，在ACS患者中，总CD4(+)和CD4(+)CD28(null)细胞上的CD31表达降低（P < 0.001，ACS与SA相比），在初始T细胞上降低（P < 0.001，ACS与SA相比），在中枢记忆和效应记忆CD4(+) T细胞上也降低（P < 0.05，ACS与SA及对照相比）。CD31对CD4(+)和CD4(+)CD28(null) T细胞TCR信号传导的免疫调节作用在ACS患者中低于SA患者（两次比较P均< 0.05）。在1年随访时，ACS患者的CD31表达和功能增加，变得与SA患者相似。ACS患者免疫突触中CD31的募集低于对照者（P = 0.012）。此外，CD31调节丝裂原活化蛋白激酶（MAPK）信号传导，并降低Th1和Th17分化所需的T-bet和Rorγ-t的表达。最后，我们研究了CD31(+)初始和致敏T细胞亚群中的TCR信号传导，观察到不同的蛋白磷酸化模式。SA中CD31介导的调节途径增强，而在ACS中暂时下调。由于CD31通过提高TCR刺激阈值来调节T细胞活化和T细胞分化，它可能是治疗ACS中T细胞异常的新分子靶点。
