Kasahara Kazuyuki, Sasaki Naoto, Amin Hilman Zulkifli, Tanaka Toru, Horibe Sayo, Yamashita Tomoya, Hirata Ken-Ichi, Rikitake Yoshiyuki
Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA.
Heliyon. 2022 Jul 19;8(7):e09981. doi: 10.1016/j.heliyon.2022.e09981. eCollection 2022 Jul.
Compelling evidence suggests a crucial role for Foxp3 regulatory T cells (Tregs) in the control of atherosclerosis. Although suppression of pro-inflammatory CD4 T cell immune responses is supposed to be important for athero-protective action of Foxp3 Tregs, few studies have provided direct evidence for this protective mechanism. We investigated the impact of Foxp3 Treg depletion on CD4 T cell immune responses and the development of atherosclerosis under hypercholesterolemia. We employed DEREG (depletion of regulatory T cells) mice on an atherosclerosis-prone low-density lipoprotein receptor-deficient ( ) background, which carry a diphtheria toxin (DT) receptor under the control of the gene locus. In these mice, DT injection led to efficient depletion of Foxp3 Tregs in spleen, lymph nodes and aorta. Depletion of Foxp3 Tregs augmented CD4 effector T cell immune responses and aggravated atherosclerosis without affecting plasma lipid profile. Notably, the proportion of pro-inflammatory IFN-γ-producing T cells were increased in spleen and aorta following Foxp3 Treg depletion, implying that Foxp3 Tregs efficiently regulate systemic and aortic T cell-mediated inflammatory responses under hypercholesterolemia. Unexpectedly, Foxp3 Treg depletion resulted in an increase in anti-inflammatory IL-10-producing T cells, which was not sufficient to suppress the augmented proinflammatory T cell immune responses caused by reduced numbers of Foxp3 Tregs. Our data indicate that Foxp3 Tregs suppress pro-inflammatory CD4 T cell immune responses to control atherosclerosis under hypercholesterolemia.
有力证据表明，Foxp3调节性T细胞（Tregs）在动脉粥样硬化的控制中起关键作用。尽管抑制促炎性CD4 T细胞免疫反应被认为对Foxp3 Tregs的抗动脉粥样硬化作用很重要，但很少有研究为这种保护机制提供直接证据。我们研究了在高胆固醇血症情况下，Foxp3 Treg耗竭对CD4 T细胞免疫反应和动脉粥样硬化发展的影响。我们使用了在动脉粥样硬化易感性低密度脂蛋白受体缺陷背景下的DEREG（调节性T细胞耗竭）小鼠，这些小鼠在基因位点的控制下携带白喉毒素（DT）受体。在这些小鼠中，注射DT导致脾脏、淋巴结和主动脉中Foxp3 Tregs的有效耗竭。Foxp3 Tregs的耗竭增强了CD4效应T细胞免疫反应并加重了动脉粥样硬化，而不影响血浆脂质谱。值得注意的是，Foxp3 Treg耗竭后，脾脏和主动脉中产生促炎性干扰素-γ的T细胞比例增加，这意味着在高胆固醇血症情况下，Foxp3 Tregs有效地调节全身和主动脉中T细胞介导的炎症反应。出乎意料的是，Foxp3 Treg耗竭导致产生抗炎性白细胞介素-10的T细胞增加，但这不足以抑制因Foxp3 Tregs数量减少而增强的促炎性T细胞免疫反应。我们的数据表明，在高胆固醇血症情况下，Foxp3 Tregs抑制促炎性CD4 T细胞免疫反应以控制动脉粥样硬化。
