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

## TL;DR

This study shows that TBL1X/TBL1XR1 in CD4+ T cells helps prevent atherosclerosis by controlling inflammation and cell activity.

## Contribution

The study identifies TBL1X/TBL1XR1 as a novel regulator of CD4+ T cell function in atherosclerosis.

## Key findings

- TBL1X/TBL1XR1 is enriched in CD4+ T cells in human atherosclerotic plaques.
- Loss of TBL1X/TBL1XR1 in CD4+ T cells increases atherosclerosis in mice.
- Reduced TBL1X/TBL1XR1 is linked to unstable human carotid plaques.

## Abstract

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 CD44lowCD62Lhi cells to CD44hiCD62Llow 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 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; CD4+ T-cell depletion expands effector, regulatory cells and cytokine.•TBL1X/TBL1XR1 control inflammatory and redox programs; transcriptomics show AP-1 and ATF3 pathway activation in CD4+ T cells.•Deficiency promotes atherosclerosis without metabolic change; in LDLR-/- chimeras KO doubles arch lesions, not other sites.•In unstable human carotid plaques, reduced TBL1X/TBL1XR1 expression highlights these cofactors as potential treatment target.

Plaque T cells 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; CD4+ T-cell depletion expands effector, regulatory cells and cytokine.

TBL1X/TBL1XR1 control inflammatory and redox programs; transcriptomics show AP-1 and ATF3 pathway activation in CD4+ T cells.

Deficiency promotes atherosclerosis without metabolic change; in LDLR-/- chimeras KO doubles arch lesions, not other sites.

In unstable human carotid plaques, reduced TBL1X/TBL1XR1 expression highlights these cofactors as potential treatment target.