Objective— The purpose of this study was to determine the effects of an atherogenic diet on immune function in LDLr^−/−, ApoA-I^−/− mice.

Methods and Results— When LDLr^−/−, ApoA-I^−/− (DKO), and LDLr^−/− (SKO) mice were fed an atherogenic diet, DKO had larger peripheral lymph nodes (LNs) and spleens compared to SKO mice. LNs were enriched in cholesterol and contain expanded populations of T, B, dendritic cells, and macrophages. Expansion of all classes of LN cells was accompanied by a ≈1.5-fold increase in T cell proliferation and activation. Plasma antibodies to dsDNA, β2-glycoprotein I, and oxidized LDL were increased in DKO, similar to levels in diet-fed Fas^lpr/lpr mice, suggesting the development of an autoimmune phenotype. Both LN enlargement and cellular cholesterol expansion were “prevented” when diet-fed DKO mice were treated with helper dependent adenovirus expressing apoA-I. Independent of the amount of dietary cholesterol, DKO mice consistently showed lower plasma cholesterol than SKO mice, yet greater aortic cholesterol deposition and inflammation.

Conclusions— ApoA-I prevented cholesterol-associated lymphocyte activation and proliferation in peripheral LN of diet-fed DKO mice. A ≈1.5-fold increase in T cell activation and proliferation was associated with a ≈3-fold increase in concentrations of circulating autoantibodies and ≈2-fold increase in the severity of atherosclerosis suggesting a common link between plasma apoA-I, inflammation, and atherosclerosis.