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

doi:10.1016/j.heliyon.2022.e09981

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

Heliyon. 2022 Jul 19;8(7):e09981. doi: 10.1016/j.heliyon.2022.e09981. eCollection 2022 Jul.

Authors

Kazuyuki Kasahara^{1

2}, Naoto Sasaki^{1

3}, Hilman Zulkifli Amin³, Toru Tanaka³, Sayo Horibe³, Tomoya Yamashita¹, Ken-Ichi Hirata¹, Yoshiyuki Rikitake³

Affiliations

¹ 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.
² Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA.
³ Laboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.

Abstract

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.

Keywords: Atherosclerosis; CD4+ T cells; Immunology; Inflammation; Regulatory T cells.