Apolipoprotein A-I modulates regulatory T cells in autoimmune LDLr-/-, ApoA-I-/- mice.
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.
Wilhelm
Ashley J
AJ
Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Zabalawi
Manal
M
Owen
John S
JS
Shah
Dharika
D
Grayson
Jason M
JM
Major
Amy S
AS
Bhat
Shaila
S
Gibbs
Dwayne P
DP
Thomas
Michael J
MJ
Sorci-Thomas
Mary G
MG
D000818:Animals; D016632:Apolipoprotein A-I / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D039521:CD11c Antigen / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D008076:Cholesterol, HDL / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004036:Diet, Atherogenic; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007279:Injections, Subcutaneous; D008055:Lipids / Q000032:analysis; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
D016632:Apolipoprotein A-I; D039521:CD11c Antigen; D017252:CD3 Complex; D008076:Cholesterol, HDL; D008055:Lipids; D011973:Receptors, LDL