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T cells expressing the lupus susceptibility allele Pbx1d enhance autoimmunity and atherosclerosis in dyslipidemic mice
Wei Li, … , Amy Major, Laurence Morel
Wei Li, … , Amy Major, Laurence Morel
Published June 4, 2020
Citation Information: JCI Insight. 2020;5(11):e138274. https://doi.org/10.1172/jci.insight.138274.
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Research Article Cardiology

T cells expressing the lupus susceptibility allele Pbx1d enhance autoimmunity and atherosclerosis in dyslipidemic mice

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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.

Authors

Wei Li, Ahmed S. Elshikha, Caleb Cornaby, Xiangyu Teng, Georges Abboud, Josephine Brown, Xueyang Zou, Leilani Zeumer-Spataro, Brian Robusto, Seung-Chul Choi, Kristianna Fredenburg, Amy Major, Laurence Morel

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Figure 1

Sle1 partially accounts for the atherogenic effect of TC immune cells.

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Sle1 partially accounts for the atherogenic effect of TC immune cells.
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(A) Experimental design. (B) Representative images of atherosclerotic lesions in the aortic root for each of the 3 groups and (C) corresponding morphometric analysis. (D) Terminal serum cholesterol. (E) Morphometric analysis of CD4+ T cell infiltrates in the aortic root. Terminal serum anti-dsDNA IgG (F) and oxLDL IgG (G). Means ± SEM compared with 1-way ANOVA with Tukey’s multiple-comparisons tests. *P < 0.05, ***P < 0.001. Each symbol represents 1 mouse.

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