Abstract
Patients with systemic lupus erythematosus (SLE) present a high incidence of atherosclerosis, which contributes significantly to morbidity and mortality in this autoimmune disease. An impaired balance between regulatory (Treg) and follicular helper (Tfh) CD4+ T cells is shared by both diseases. However, whether there are common mechanisms of CD4+ T cell dysregulation between SLE and atherosclerosis remains unclear. Pre-B cell leukemia transcription factor 1 isoform d (Pbx1d) is a lupus susceptibility gene that regulates Tfh cell expansion and Treg cell homeostasis. Here, we investigated the role of T cells overexpressing Pbx1d in low-density lipoprotein receptor-deficient (Ldlr-/-) mice fed with a high-fat diet, an experimental model for atherosclerosis. Pbx1d-transgenic T cells exacerbated some phenotypes of atherosclerosis, which were associated with higher autoantibody production, increased Tfh cell frequency, and impaired Treg cell regulation, in Ldlr-/- mice as compared with control T cells. In addition, we showed that dyslipidemia and Pbx1d-transgenic expression independently impaired the differentiation and function of Treg cells in vitro, suggesting a gene/environment additive effect. Thus, our results suggest that the combination of Pbx1d expression in T cells and dyslipidemia exacerbates both atherosclerosis and autoimmunity, at least in part through a dysregulation of Treg cell homeostasis.
Highlights
As the underlying cause of heart attacks and strokes, atherosclerosis is one of the leading causes of death worldwide
The Sle1 bone marrow–derived (BM-derived) cells were, not sufficient to induce autoantibodies against dsDNA or oxidized LDL (Figure 1, F and G) to the same level as triple congenic (TC) BM-derived cells. These results indicate that immune cells expressing Sle1 promote atherosclerosis at least in part through CD4+ T cells, independent of autoantibody and overt autoimmunity as observed in TC recipients
Using the TC mouse model of lupus, it was determined that CD4+ T cells are responsible for the atherosclerotic effect [8]
Summary
As the underlying cause of heart attacks and strokes, atherosclerosis is one of the leading causes of death worldwide. It has been recently reported that dyslipidemia exacerbates SLE pathogenesis with enhanced follicular helper T (Tfh) cell responses [6], while transferring CD4+ T cells from lupus-prone mice into dyslipidemic mice accelerates the development of atherosclerosis [7, 8]. These results suggest that CD4+ T cells represent a functional link in a reciprocal enhancement between SLE and atherosclerosis. There is a growing interest in identifying common mechanisms by which CD4+ T cells induce pathogenesis in both SLE and atherosclerosis
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