Role of Naturally Occurring CD4 ⁺ CD25 ⁺ Regulatory T Cells in Experimental Atherosclerosis

Abstract

Objective-Naturally occurring CD4ϩ CD25 ϩ regulatory T cells (Tregs) exert suppressive effects on effector CD4 cells and downregulate experimental autoimmune disorders. We investigated the importance and potential role of Tregs in murine atherogenesis. Methods and Results-Tregs were investigated comparatively between aged and young apolipoprotein E-knockout (ApoE-KO) mice and age-matched C57BL/6 littermates. The effect of oxidized LDL (oxLDL) was tested on the functional suppressive properties of Tregs from ApoE-KO and C57BL/6 mice. Tregs, CD4 ϩ CD25 Ϫ cells, and saline were infused into ApoE-KO mice to study their effects on atherogenesis. Treg numbers were reduced in atherosclerotic compared with nonatherosclerotic ApoE-KO mice. The functional suppressive properties of Tregs from ApoE-KO mice were compromised in comparison with those from their C57BL/6 littermates. Thus, oxLDL attenuated the suppressive properties of Tregs from C57BL/6 mice and more so in ApoE-KO mice. Transfer of Tregs from age-matched ApoE-KO mice resulted in significant attenuation of atherosclerosis compared with that after delivery of CD4 ϩ CD25 ϩ/Ϫ T cells or phosphate-buffered saline. Conclusions-CD4ϩ CD25 ϩ Tregs may play a protective role in the progression of atherosclerosis and could be considered a therapeutic tool if results from human studies can solidify observations in murine models.

Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

“…It is clear that an imbalance in the ratio of T regulatory (T R ) and T effector (T E ) cells can be an important cause of autoimmunity (36) and that CD4 ϩ T R cells play a protective role in the progression of atherosclerosis (37,38). In addition to direct suppressive activity, IL-35 is able, like the other immunosuppressive cytokines TGF-␤1 and IL-10, to expand the breadth of suppressive immunity by inducing and mobilizing additional regulatory cells in a process known as infectious tolerance (24,39).…”

Higher expression of Bax in regulatory T cells increases vascular inflammation

“…CD4+CD25 high Foxp3+ regulatory T cells (Tregs), comprising 5-10% of CD4+ T cells(1), exhibit potent immunosuppressive functions(2) in the regulation of autoimmunity and inflammatory atherosclerosis (3,4). Naturally occurring Treg cells (thymus-generated, nTreg cells), as an independent subset, are engaged in the maintenance of immunological selftolerance and inhibition of various immune responses (5) and inflammatory atherogenesis.…”

“…Tregs play an important role in controlling the pathogenesis of inflammatory atherosclerosis (3,4). In addition, IL-2 knock-out mice have a deficiency in Tregs, and spontaneously develop autoimmune diseases including vasculitis (12).…”

Impact of environmental factors on alloimmunity and transplant fate

“…Moreover, the reciprocal crosstalk between the immune system and the microbiota implies that the alloimmune response and the immunosuppressive drugs taken by transplant hosts may trigger additional feedback loops between microbial changes and the strength of the alloimmune response, eventually impacting graft outcome. (81). T cells from hyperlipidemic mice expressed significantly lower levels of the proapoptotic molecule Bim, which has previously been implicated in Treg function, compared with normal mice (82).…”