Apolipoprotein A-I modulates regulatory T cells in autoimmune LDLr-/-, ApoA-I-/- mice. J Biol Chem 2010 Nov 12;285(46):36158-69
Date
09/14/2010Pubmed ID
20833724Pubmed Central ID
PMC2975238DOI
10.1074/jbc.M110.134130Scopus ID
2-s2.0-77958478114 (requires institutional sign-in at Scopus site) 107 CitationsAbstract
The immune system is complex, with multiple layers of regulation that serve to prevent the production of self-antigens. One layer of regulation involves regulatory T cells (Tregs) that play an essential role in maintaining peripheral self-tolerance. Patients with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis have decreased levels of HDL, suggesting that apoA-I concentrations may be important in preventing autoimmunity and the loss of self-tolerance. In published studies, hypercholesterolemic mice lacking HDL apoA-I or LDLr(-/-), apoA-I(-/-) (DKO), exhibit characteristics of autoimmunity in response to an atherogenic diet. This phenotype is characterized by enlarged cholesterol-enriched lymph nodes (LNs), as well as increased T cell activation, proliferation, and the production of autoantibodies in plasma. In this study, we investigated whether treatment of mice with lipid-free apoA-I could attenuate the autoimmune phenotype. To do this, DKO mice were first fed an atherogenic diet containing 0.1% cholesterol, 10% fat for 6 weeks, after which treatment with apoA-I was begun. Subcutaneous injections of 500 μg of lipid-free apoA-I was administered every 48 h during the treatment phase. These and control mice were maintained for an additional 6 weeks on the diet. At the end of the 12-week study, DKO mice showed decreased numbers of LN immune cells, whereas Tregs were proportionately increased. Accompanying this increase in Tregs was a decrease in the percentage of effector/effector memory T cells. Furthermore, lipid accumulation in LN and skin was reduced. These results suggest that treatment with apoA-I reduces inflammation in DKO mice by augmenting the effectiveness of the LN Treg response.
Author List
Wilhelm AJ, Zabalawi M, Owen JS, Shah D, Grayson JM, Major AS, Bhat S, Gibbs DP Jr, Thomas MJ, Sorci-Thomas MGAuthors
Mary Sorci Thomas PhD Professor in the Medicine department at Medical College of WisconsinMichael J. Thomas PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsApolipoprotein A-I
Autoimmunity
CD11c Antigen
CD3 Complex
Cell Proliferation
Cholesterol, HDL
Dendritic Cells
Diet, Atherogenic
Female
Flow Cytometry
Humans
Injections, Subcutaneous
Lipids
Lymph Nodes
Lymphocyte Activation
Lymphocyte Count
Macrophages
Male
Mice
Mice, Inbred C57BL
Microscopy, Fluorescence
Receptors, LDL
Skin
T-Lymphocytes, Regulatory
