The Atheroprotective Effect of 17β-Estradiol Depends on Complex Interactions in Adaptive Immunity

Estradiol prevents fatty streak formation in chow-fed atherosclerosis-prone apolipoprotein E (ApoE)-deficient mice. We previously reported that fatty streak development of immunodeficient ApoE−/−/recombination activating gene 2 (RAG-2−/−) double-deficient mice was insensitive to estradiol. In the present work, we demonstrate that the reconstitution of ApoE−/−/RAG-2−/− with bone marrow from immunocompetent ApoE−/−/RAG-2+/+ mice restores the protective effect of estradiol on fatty streak constitution. We extended this demonstration to the model of low-density lipoprotein receptor-deficient mice, establishing the obligatory role of mature lymphocytes in this process. We then investigated whether the protective effect of estradiol was mediated by a specific lymphocyte subpopulation by studying the hormonal effect on fatty streak constitution in recently developed models of ApoE−/− mice deficient in selective T-lymphocyte subsets (either TCRαβ+, CD4+, CD8+, or TCRγδ+ lymphocytes) or B lymphocytes. In all these specifically immunodeficient mice, estradiol administration to ovariectomized mice conferred protection as in immunocompetent ApoE−/− mice, clearly demonstrating that no single lymphocyte subpopulation was specifically required for this effect. These results point to additional lymphocyte-dependent mechanisms such as modulating the interactions among lymphocytes and between lymphocytes and endothelial and/or antigen-presenting cells.