CD4(+) T cells carry disease-promoting immunity in atherosclerosis.
Regulatory T cells (T reg cells) play a major role in controlling the pathogenic autoimmune process in type 1 diabetes (T1D). Interleukin 2 (IL-2), a cytokine which promotes T reg cell survival and function, may thus have therapeutic efficacy in T1D. We show that 5 d of low-dose IL-2 administration starting at the time of T1D onset can reverse established disease in NOD (nonobese diabetic) mice, with long-lasting effects. Low-dose IL-2 increases the number of T reg cells in the pancreas and induces expression of T reg cell–associated proteins including Foxp3, CD25, CTLA-4, ICOS (inducible T cell costimulator), and GITR (glucocorticoid-induced TNF receptor) in these cells. Treatment also suppresses interferon γ production by pancreas-infiltrating T cells. Transcriptome analyses show that low-dose IL-2 exerts much greater influence on gene expression of T reg cells than effector T cells (T eff cells), suggesting that nonspecific activation of pathogenic T eff cells is less likely. We provide the first preclinical data showing that low-dose IL-2 can reverse established T1D, suggesting that this treatment merits evaluation in patients with T1D.
Adaptive and innate immunity have been implicated in the pathogenesis of atherosclerosis. Given their abundance in the lesion, lipids might be targets of the atherosclerosis-associated immune response. Natural killer T (NKT) cells can recognize lipid antigens presented by CD1 molecules. We have explored the role of CD1d-restricted NKT cells in atherosclerosis by using apolipoprotein E–deficient (apoE−/−) mice, a hypercholesterolemic mouse model that develops atherosclerosis. ApoE−/− mice crossed with CD1d−/− (CD1d−/−apoE−/−) mice exhibited a 25% decrease in lesion size compared with apoE−/− mice. Administration of α-galactosylceramide, a synthetic glycolipid that activates NKT cells via CD1d, induced a 50% increase in lesion size in apoE−/− mice, whereas it did not affect lesion size in apoE−/−CD1d−/− mice. Treatment was accompanied by an early burst of cytokines (IFNγ, MCP-1, TNFα, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNγ and IL-4 transcripts in the spleen and aorta. Early activation of both T and B cells was followed by recruitment of T and NKT cells to the aorta and activation of inflammatory genes. These results show that activation of CD1d-restricted NKT cells exacerbates atherosclerosis.
These data show reduced atherosclerosis and Th1 activity in spite of increased serum cholesterol in IL-18 deficient apoE(-/-) mice. They support a proatherogenic role for IL-18.
CD4 + CD25 + Foxp3 + Tregs play a major role in prevention of autoimmune diseases. The suppressive effect of Tregs on effector T cells (Teffs), the cells that can mediate autoimmunity, has been extensively studied. However, the in vivo impact of Teff activation on Tregs during autoimmunity has not been explored. In this study, we have shown that CD4 + Teff activation strongly boosts the expansion and suppressive activity of Tregs. This helper function of CD4 + T cells, which we believe to be novel, was observed in the pancreas and draining lymph nodes in mouse recipients of islet-specific Teffs and Tregs. Its physiological impact was assessed in autoimmune diabetes. When islet-specific Teffs were transferred alone, they induced diabetes. Paradoxically, when the same Teffs were cotransferred with islet-specific Tregs, they induced disease protection by boosting Treg expansion and suppressive function. RNA microarray analyses suggested that TNF family members were involved in the Teff-mediated Treg boost. In vivo experiments showed that this Treg boost was partially dependent on TNF but not on IL-2. This feedback regulatory loop between Teffs and Tregs may be critical to preventing or limiting the development of autoimmune diseases.
Background-The cytokines interleukin 1 (IL-1) and tumor necrosis factor (TNF) are secreted by the different cell populations of the vascular wall and have been suggested to promote atherosclerosis. Methods and Results-Their respective roles in fatty-streak formation in apolipoprotein E-deficient mice were investigated by use of IL-1 receptor antagonist and TNF binding protein. Estradiol-17 was used as a positive control. Blocking TNF seemed to be active in female animals but not in males. IL-1 receptor antagonist was as effective as or more effective than estradiol in both sexes. Conclusions-IL-1 plays a crucial role in the initial step of the atherosclerotic process in this animal model, and blocking the activity of this cytokine should be considered as a therapeutic possibility. (Circulation. 1998;97:242-244.)Key Words: atherosclerosis Ⅲ apolipoproteins Ⅲ interleukins Ⅲ tumor necrosis factor I t is known that IL-1␣ and -1 and TNF-␣ and - are secreted in the vascular wall by endothelial and smooth muscle cells as well as by monocytes/macrophages. 1,2 These cytokines have been shown to increase permeability of the endothelial cell barrier, 3 induce the expression of surface leukocyte adhesion molecules, 1,4,5 and enhance the production of other cytokines and growth factors, such as IL-6 6 and macrophage colony-stimulating factor, 7-9 all such activities being considered to promote atherosclerosis. The objective of the present study was therefore to clarify the role of IL-1 and TNF in the initial steps of the atherosclerotic process, ie, fatty-streak formation, using apo E KO mice as an animal model of atherosclerosis 10,11 and human IL-1ra and TNFbp as the specific cytokine antagonists. IL-1ra is a recombinant 17-kD protein, which binds to IL-1 receptors and competes with both IL-1␣ and IL-1 without detectable IL-1 agonistic effects. 12,13 TNFbp is a specific TNF inhibitor consisting of two molecules of the extracellular domain of the human type 1 TNF receptor added to both ends of a molecule of polyethylene glycol. TNFbp binds with equal affinity to TNF-␣ and TNF-.14 -16 E 2 treatment was used as a positive control, because we and others have shown that this hormone prevents fatty-streak formation in the apo E KO mouse animal model. 17,18 The data obtained showed that TNFbp was active in female animals but not in males. Like E 2 , IL-1ra was active in both sexes, suggesting that IL-1 plays a crucial role in the initial step of the atherosclerotic process in this animal model. Methods Study ProtocolApo E KO mice, originally obtained from the Jackson Laboratory, Bar Harbor, Me (sixth generation of backcross from 129/B6 F1 heterozygous to C57BL/6), were housed as previously described 18 and fed normal laboratory mouse chow containing 4.3% fat and 0.02% cholesterol. Four-week-old animals were gonadectomized under general anesthesia. At 2 months of age, these animals were given 0.2 mg 60-day time-release E 2 pellets (Innovative Research of America), a dose that was found to exert a maximal effect on fatty-strea...
The reality of the atheroprotective effect of estrogens is still a matter of debate, and its unknown mechanisms could involve favorable changes in blood lipids and lipoproteins and/or direct action at the level of the arterial wall. We used the recently developed animal model of atherosclerosis constituted by apolipoprotein E-deficient mice in an attempt to clarify these issues. Male and female animals, fed a low-fat chow diet, were treated with increasing doses of 17 beta-estradiol (E2) after castration and compared with testosterone treated and uncastrated (intact) animals. Total serum cholesterol, LDL-cholesterol, and HDL-cholesterol concentrations decreased under E2 treatment in each sex and were weakly correlated with lesion area. However, a highly significant correlation between lesion area and serum E2 levels also suggested a direct action of E2 on cells of the vascular wall. A dose-response curve analysis revealed that these activities were sex-dependent, with females being nearly twice as sensitive to E2 as males. It also revealed that the atheroprotective activity was recruited at higher E2 concentrations than those needed by other E2 target tissues such as uterus or functions such as apoA-1 and LDL production and/or clearance rates.
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