Lipid challenge negatively affects macroautophagy and results in reduced CD4+ T cell function

Abstract

The world is currently suffering from an epidemic of obesity, likely due to the "western diet" high in fat, sugar and cholesterol, that has become a major public health issue, especially in developed countries. Obesity is associated with changes in the immune compartment that significantly hinder the response against infection. Previous studies have reported a dysregulation of immune responses as a consequence of high lipid loads; however, the cellular processes that are affected by lipid stress are still not completely understood. Autophagy is an essential catabolic process through which cellular components are degraded by the lysosomal machinery. In T cells, autophagy is an actively regulated process that is necessary to sustain T cell activation. The overall goal of my thesis project is to elucidate if a potential dysregulation of autophagy caused by lipid challenge could be responsible for an inefficient activation of T cells, and consequently a defective adaptive immune response.;We have performed in vitro assays to assess human and murine CD4+ T cell responses when challenged with increasing concentrations of saturated or unsaturated fatty acids. These experiments show a decrease in T cell receptor activation-induced cell proliferation and cytokine secretion in a dose-dependent manner. Interestingly, correlating with the functional defect induced by lipid challenge, T cells show also a concentration-dependent decrease in TCR-induced autophagy activation. Our data indicate that lipid challenge leads to reduced autophagosome formation and altered lysosome fusion, which correlates with a profound change in the lipid content of T cells when exposed to increasing concentrations of fatty acids. In vivo studies using mice subjected to high-fat diet confirm that a high lipid load inhibits activation-induced autophagy in CD4 + T cells, which results in reduced activation-induced responses. We have shown that these lipid challenge-induced defects in T cell function are not the result of decreased TCR signaling, nor increased apoptosis, rather seem to result from a defective autophagy. Indeed, when Atg7-deficient cells, unable to activate autophagy, are challenged with oleic acid, this fatty acid does not induce a further decrease in their function. These results support the conclusion that the direct effect of lipids on autophagy is a major mechanism that accounts for the decrease in T cell function induced by lipid stress. Functional defects in CD4+ T cells and autophagy activity caused by lipid challenge appear to be reversible in vitro by a recovery period in the absence of excess lipid exposure, and in vivo when high fat diet-fed mice return to a control diet with reduced fat content.;Our results indicate that increased lipid load can dysregulate autophagy and cause defective T cell responses. Furthermore, they suggest that a decreased ability of CD4+ T cells to respond to infection in obese individuals may be caused by defects in autophagy in these cells, which would underlie some of the characteristic obesity-associated defects in the T cell compartment.