Depletion of Foxp3(+) regulatory T cells augments CD4(+) T cell immune responses in atherosclerosis-prone hypercholesterolemic mice

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 atheroprotective 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 (Ldlr(-/-)) background, which carry a diphtheria toxin (DT) receptor under the control of the foxp3 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-gamma-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-roducing 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.

Automated summary

This study demonstrates that Foxp3(+) Tregs can suppress pro-inflammatory CD4(+) T cell immune responses to control the development of atherosclerosis under hypercholesterolemia.