Atherosclerosis Impairs Naive CD4 T-Cell Responses via Disruption of Glycolysis.

Objective CD4 T cells are important regulators of atherosclerotic progression. The metabolic profile of CD4 T cells controls their signaling and function, but how atherosclerosis affects T-cell metabolism is unknown. Here, we sought to determine the impact of atherosclerosis on CD4 T-cell metabolism and the contribution of such alterations to atheroprogression. Approach and Results: Using PCR arrays, we profiled the expression of metabolism genes in CD4 T cells from atherosclerotic, apolipoprotein-E knockout mice fed a Western diet. These cells exhibited dysregulated expression of genes critically involved in glycolysis and fatty acid degradation, compared with those from animals fed a standard laboratory diet. We examined how T-cell metabolism was changed in standard laboratory diet or Western diet-fed apolipoprotein-E knockout mice or humans by measuring glucose uptake, activation, and proliferation in CD4 T cells. We found that naive CD4 T cells from Western diet-fed apolipoprotein-E knockout mice failed to uptake glucose and thus displayed impaired proliferation and activation, compared with CD4 T cells from standard laboratory diet-fed animals. Similarly, as in mice, we observed that naive CD4 T-cell frequencies were reduced in circulation of human subjects with high cardiovascular disease compared with low cardiovascular disease, as assessed clinically based on medically necessary coronary angiography. Naive T cells from high cardiovascular disease subjects also showed reduced proliferative capacity. Conclusions These results highlight the dysfunctional changes that occur in CD4 T-cell metabolism and immune responses during atherosclerosis. Targeting metabolic pathways within naive CD4 T cells could thus yield novel therapeutic approaches for improving CD4 T-cell responses against atheroprogression.