Legumain deficiency halts atherogenesis by modulating T cell receptor signaling.

Abstract

Atherosclerosis is an age-related pathological process associated with elevated levels of legumain in plaques and plasma. However, the underlying mechanisms remain unclear. The aim of this study was to investigate the role of legumain in the progression of atherosclerotic plaques, with a particular focus on functional and phenotypic changes in CD4⁺ T cells. Apolipoprotein E-deficient (Apoe^-/-) mice were crossed with legumain-deficient (Lgmn^-/-) mice to generate Lgmn^-/-Apoe^-/- mice. CD4⁺ T cells accumulated in the atherosclerotic plaques of Apoe^-/- mice fed a high-fat diet. Deletion of legumain attenuated the deposition of CD4⁺ T cells in plaques and reduced the number of atherosclerotic lesions. The levels of CD4⁺ T cells in the blood, lymph nodes, and spleen were decreased in Lgmn^-/- mice. Transcriptomic analysis revealed that the deletion of legumain decreased the differentiation, survival, and function of CD4⁺ memory T cells by suppressing the T cell receptor (TCR) signaling pathway. These changes are accompanied by the downregulation of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) and the reduced release of interleukin (IL)-2 and interferon (IFN)-γ. These results suggest that legumain deficiency may play a role in the development of atherosclerosis by impairing the survival, proliferation, and function of CD4⁺ T cells. Inhibition of legumain activity may be an innovative therapy for the treatment of atherosclerosis.