Impaired up-regulation of CD25 on CD4+ T cells in IFN-γ knockout mice is associated with progression of myocarditis to heart failure
Impaired up-regulation of CD25 on CD4+ T cells in IFN-γ knockout mice is associated with progression of myocarditis to heart failure
复制标题
DOI：
10.1073/pnas.0408241102
复制
发表时间：
2005-01-04
影响因子：
11.1
通讯作者：
Rose, NR
中科院分区：
文献类型：
--
作者：
Afanasyeva, M;Georgakopoulos, D;Rose, NR
炎症已被越来越多地认为是许多心脏疾病的重要病理组成部分。建立了小鼠自身免疫性心肌炎模型，以研究免疫介质在心功能不全发生中的作用。我们以前已经发现，IFN-γ缺乏促进小鼠心肌炎的炎症。然而，目前尚不清楚心肌炎中IFN-γ缺乏如何影响心脏功能，以及这些影响的潜在免疫机制是什么。在这项工作中，我们表明，IFN-γ基因敲除（KO）小鼠有更明显的收缩和舒张功能障碍和更大的频率发展为扩张型心肌病和心力衰竭相比，野生型小鼠。KO小鼠的心功能障碍与活化的（CD 44（高））CD 3（+）T细胞的扩增有关，这是由于CD 4（+）T细胞而不是CD 8（+）T细胞的凋亡减少。KO小鼠中的CD 4（+）T细胞在活化后显示出受损的CD 25上调，导致CD 4（+）CD 44（+）CD 25（-）T细胞扩增并浸润到心脏中。与CD 25（+）细胞群相比，CD 4（+）CD 25（-）T细胞的增殖倾向较低，它们浸润到心脏与心肌炎的严重程度更高相关。我们的结论是，自身免疫性心肌炎中IFN-γ缺乏与CD 4（+）CD 44（+）CD 25（-）T细胞的优先扩增相关，导致心脏炎症增加。IFN-γ KO小鼠中过度的炎症反应导致心功能障碍，导致扩张型心肌病和心力衰竭。
Inflammation has been recognized increasingly as a critical pathologic component of a number of heart diseases. A mouse model of autoimmune myocarditis was developed to study the role of immune mediators in the development of cardiac dysfunction. We have found previously that IFN-gamma deficiency promotes inflammation in murine myocarditis. It has been unclear, however, how IFN-gamma deficiency in myocarditis affects cardiac function and what underlying immune mechanisms are responsible for these effects. In this work, we show that IFN-gamma knockout (KO) mice have more pronounced systolic and diastolic dysfunction and greater frequency of progression to dilated cardiomyopathy and heart failure compared with WT mice. Cardiac dysfunction in the KO mice is associated with the expansion of activated (CD44(high)) CD3(+) T cells due to reduced apoptosis of CD4(+), but not CD8(+), T cells. CD4(+) T cells in the KO mice show impaired up-regulation of CD25 upon activation, resulting in the expansion of CD4(+)CD44(+)CD25(-) T cells and their infiltration into the heart. CD4(+)CD25(-) T cells are less apoptosis-prone compared with the CD25(+) population, and their infiltration into the heart is associated with greater severity of myocarditis. We conclude that IFN-gamma deficiency in autoimmune myocarditis is associated with preferential expansion of CD4(+)CD44(+)CD25(-) T cells resulting in increased cardiac inflammation. An exaggerated inflammatory response in IFN-gamma KO mice causes cardiac dysfunction, leading to dilated cardiomyopathy and heart failure.