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

• Published in: Frontiers in immunology Vol. 9; p. 2937
• Main Authors: Amersfoort, Jacob, Douna, Hidde, Schaftenaar, Frank H, Foks, Amanda C, Kröner, Mara J, van Santbrink, Peter J, van Puijvelde, Gijs H M, Bot, Ilze, Kuiper, Johan
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 12.12.2018
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - immunology; Adaptor Proteins, Signal Transducing - metabolism; Animals; Atg7; atherosclerosis; Atherosclerosis - etiology; Atherosclerosis - immunology; Atherosclerosis - metabolism; autophagy; Autophagy - genetics; Autophagy - immunology; Autophagy-Related Protein 7 - deficiency; Autophagy-Related Protein 7 - genetics; Autophagy-Related Protein 7 - immunology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cytokines - immunology; Cytokines - metabolism; Diet, Western - adverse effects; Fatty Liver - etiology; Fatty Liver - immunology; Fatty Liver - metabolism; Female; Immunology; Liver - immunology; Liver - metabolism; Liver - pathology; Mice, Knockout; Mice, Transgenic; steatosis; T cells; atherosclerosis; autophagy; Atg7; T cells; steatosis
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2018.02937

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 ) had a diminished naïve CD4 and CD8 T cell compartment in the spleen and mediastinal lymph node as compared to littermate controls (Atg7 ). Lck-Cre Atg7 and Atg7 mice were injected intravenously with rAAV2/8-D377Y-mPCSK9 and fed a Western-type diet to induce atherosclerosis. While Lck-Cre Atg7 mice had equal serum Proprotein Convertase Subtilisin/Kexin type 9 levels as compared to Atg7 mice, serum cholesterol levels were significantly diminished in Lck-Cre Atg7 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 mice as compared to Atg7 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.