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 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.