Defective Autophagy in T Cells Impairs the Development of Diet-Induced Hepatic Steatosis and Atherosclerosis

Abstract

Macroautophagy (or autophagy) is a conserved cellular process in which cytoplasmic cargo is targeted for lysosomal degradation. Autophagy is crucial for the functional integrity of different subsets of T cells in various developmental stages. Since atherosclerosis is an inflammatory disease of the vessel wall which is partly characterized by T cell mediated autoimmunity, we investigated how advanced atherosclerotic lesions develop in mice with T cells that lack autophagy-related protein 7 (Atg7), a protein required for functional autophagy. Mice with a T cell-specific knock-out of Atg7 (Lck-Cre Atg7^f/f) had a diminished naïve CD4⁺ and CD8⁺ T cell compartment in the spleen and mediastinal lymph node as compared to littermate controls (Atg7^f/f). Lck-Cre Atg7^f/f and Atg7^f/f mice were injected intravenously with rAAV2/8-D377Y-mPCSK9 and fed a Western-type diet to induce atherosclerosis. While Lck-Cre Atg7^f/f mice had equal serum Proprotein Convertase Subtilisin/Kexin type 9 levels as compared to Atg7^f/f mice, serum cholesterol levels were significantly diminished in Lck-Cre Atg7^f/f mice. Histological analysis of the liver revealed less steatosis, and liver gene expression profiling showed decreased expression of genes associated with hepatic steatosis in Lck-Cre Atg7^f/f mice as compared to Atg7^f/f mice. The level of hepatic CD4⁺ and CD8⁺ T cells was greatly diminished but both CD4⁺ and CD8⁺ T cells showed a relative increase in their IFNγ and IL-17 production upon Atg7 deficiency. Atg7 deficiency furthermore reduced the hepatic NKT cell population which was decreased to < 0.1% of the lymphocyte population. Interestingly, T cell-specific knock-out of Atg7 decreased the mean atherosclerotic lesion size in the tri-valve area by over 50%. Taken together, T cell-specific deficiency of Atg7 resulted in a decrease in hepatic steatosis and limited inflammatory potency in the (naïve) T cell compartment in peripheral lymphoid tissues, which was associated with a strong reduction in experimental atherosclerosis.

Keywords: Atg7; T cells; atherosclerosis; autophagy; steatosis.