Xu Maria M, Murphy Patrick A, Vella Anthony T
Department of Immunology, School of Medicine, University of Connecticut Health School of Medicine , Farmington, Connecticut.
Center for Vascular Biology, University of Connecticut Health School of Medicine , Farmington, Connecticut.
Am J Physiol Heart Circ Physiol. 2019 Jun 1;316(6):H1354-H1365. doi: 10.1152/ajpheart.00148.2019. Epub 2019 Mar 29.
Atherosclerosis is a chronic inflammatory pathology that precipitates substantial morbidity and mortality. Although initiated by physiological patterns of low and disturbed flow that differentially prime endothelial cells at sites of vessel branch points and curvature, the chronic, smoldering inflammation of atherosclerosis is accelerated by comorbidities involving inappropriate activation of the adaptive immune system, such as autoimmunity. The innate contributions to atherosclerosis, especially in the transition of monocyte to lipid-laden macrophage, are well established, but the mechanisms underpinning the infiltration, persistence, and effector dynamics of CD8 T cells in particular are not well understood. Adaptive immunity is centered on a classical cascade of antigen recognition and activation, costimulation, and effector cytokine secretion upon recall of antigen. However, chronic inflammation can generate alternative cues that supplant this behavior pattern and promote the retention and activation of peripherally activated T cells. Furthermore, the atherogenic foci that activated immune cell infiltrate are unique lipid-laden environments that offer a diverse array of stimuli, including those of survival, antigen hyporesponsiveness, and inflammatory cytokine expression. This review will focus on how known cardiovascular comorbidities may be influencing CD8 T-cell activation and how, once infiltrated within atherogenic foci, these T cells face a multitude of cues that skew the classical cascade of T-cell behavior, highlighting alternative modes of activation that may help contextualize associations of autoimmunity, viral infection, and immunotherapy with cardiovascular morbidity.
动脉粥样硬化是一种慢性炎症性病理状态，可导致大量发病和死亡。尽管其始于血管分支点和弯曲部位内皮细胞受到低流量和紊乱血流的生理性模式影响而产生的差异激活，但动脉粥样硬化的慢性隐匿性炎症会因合并症（如自身免疫等涉及适应性免疫系统不适当激活的情况）而加速。先天性因素对动脉粥样硬化的作用，尤其是在单核细胞向脂质负载巨噬细胞转变过程中的作用，已得到充分证实，但特别是CD8 T细胞的浸润、持续存在及效应动力学的潜在机制仍未完全了解。适应性免疫以经典的抗原识别与激活、共刺激以及再次接触抗原时效应细胞因子分泌的级联反应为核心。然而，慢性炎症可产生替代信号，取代这种行为模式并促进外周激活T细胞的滞留和激活。此外，激活免疫细胞浸润的动脉粥样硬化病灶是独特的脂质负载环境，提供了多种刺激，包括生存、抗原低反应性和炎性细胞因子表达等刺激。本综述将聚焦于已知的心血管合并症如何影响CD8 T细胞激活，以及这些T细胞一旦浸润到动脉粥样硬化病灶内，如何面对众多使T细胞经典行为级联反应发生偏差的信号，突出可能有助于解释自身免疫、病毒感染和免疫治疗与心血管发病之间关联的替代激活模式。
