Depletion of Foxp3+ regulatory T cells augments CD4+ T cell immune responses in atherosclerosis-prone hypercholesterolemic mice
Kazuyuki Kasahara,
Naoto Sasaki,
Hilman Zulkifli Amin,
Toru Tanaka,
Sayo Horibe,
Tomoya Yamashita,
Ken-ichi Hirata,
Yoshiyuki Rikitake
Affiliations
Kazuyuki Kasahara
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
Naoto Sasaki
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; Laboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan; Corresponding author.
Hilman Zulkifli Amin
Laboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan
Toru Tanaka
Laboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan
Sayo Horibe
Laboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan
Tomoya Yamashita
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
Ken-ichi Hirata
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
Yoshiyuki Rikitake
Laboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan
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 (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-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.
