Nuclear receptor co-factor TBL1X/TBL1XR1 T cell activity protects against atherosclerosis

OpenAlex İngilizce

Atherosclerosis is a long-term complication of obesity and diabetes and as such a key driver of vascular dysfunction and eventually mortality in affected patients. Both aberrant lipid metabolism and inflammatory reactions promote atherosclerotic plaque development in the vessel wall by triggering a cascade of cellular events involving multiple cell types, including smooth muscle cells, monocytic macrophages, and lymphocytes. Despite its eminent impact on human health, molecular drivers of cellular dysfunction in atherosclerosis remain poorly defined and therapeutic options are scarce. Here we show by single-cell RNA sequencing that the expression of the nuclear receptor co-factors, TBL1X and TBL1XR1, was particularly prominent in the CD4 + T cell population of human carotid artery plaques. Indeed, genetic double deletion of TBL1X/TBL1XR1 in CD4 + T cells led to a substantial shift from naïve CD44 low CD62L hi cells to CD44 hi CD62L low effector and Foxp3 + Tregs. CD4 + TBL1X/TBL1XR1 KO cells exhibited enhanced cytokine production capacity upon ionomycin/PMA stimulation, correlating with the induction of pro-inflammatory and cytokine-producing transcriptional pathways in these cells. Consistently, transplantation of bone marrow from CD4 + -specific TBL1X/TBL1XR1 knock out mice into LDLR KO recipients doubled the development of atherosclerotic plaques in the aortic arch compared with wild-type bone marrow transplanted littermates. As TBL1X/TBL1XR1 expression levels were diminished in carotid arteries from patients with advanced unstable plaques compared to stable plaques or healthy controls, these data suggest that aberrant inhibition of TBL1X/TBL1XR1 in CD4 + T cells may contribute to the development of atherosclerosis in humans. Restoration of TBL1X/TBL1XR1 functionality may thus serve as a novel, druggable strategy for preventing or limiting atherosclerosis progression. • Plaque T cells preferentially express TBL1X/TBL1XR1. scRNA-seq of human carotid plaques shows enrichment of both cofactors in CD4 + T cells. • CD4-restricted TBL1X/TBL1XR1 loss skews T-cell states and cytokines. CD4 + T cell specific depletion of TBL1X/TBL1XR1 in mice increase effector and regulatory T cell populations and result in increased pro-inflammatory cytokine production. • TBL1X/TBL1XR1 governs inflammatory and redox programs. Based on transcriptomic analysis, depletion of TBL1X/TBL1XR1 activates AP-1 and ATF3-mediated inflammatory pathways in CD4 + T cells. • Deficiency promotes atherosclerosis without metabolic change. In LDLR - / - bone-marrow chimeras, KO doubles aortic-arch lesion burden; descending aorta unchanged; aortic-root lesions remain early and collagen is not different. • In unstable human carotid plaques, reduced expression of TBL1X/TBL1XR1 makes these co-factors as a potential target for the treatment of atherosclerotic plaques.