Altered Basal Lipid Metabolism Underlies the Functional Impairment of Naive CD8+ T Cells in Elderly Humans

ABSTRACT Background Aging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered antigens. The mechanisms that underlie this phenomenon have nonetheless remained unclear. Methods Biochemical and functional properties of naive CD8 + T cells were characterized and compared between middle aged and older individuals. Findings We identified an age-related link between altered basal lipid metabolism in naive CD8 + T cells and their impaired responsiveness to stimulation, characterized by low proliferative potential and susceptibility to apoptosis. Reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, improved the functional capabilities of naive CD8 + T cells in elderly subjects. Interpretation Interventions that favor lipid catabolism may find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against emerging pathogens or tumors. Funding A full list of the funding sources is detailed in the Acknowledgment section of the manuscript. RESEARCH IN CONTEXT Evidence before this study Old subjects are highly susceptible to infections and tumors and usually present with low responses to vaccine. This is mainly due to the age-related loss of primary immune resources, i.e. a quantitative decline of naive CD8 + T cells. Nonetheless, few studies have also underlined, within this cell subset, qualitative defects in elderly subjects. Added value of this study Considering the well-demonstrated link between nutrient usage and lymphocyte functions, we characterized the bioenergetics features of old naïve CD8 + T cells. Our data show an age-dependent altered basal metabolism in this cell subset, mostly at the levels of fatty acids and mitochondrial functions. These alterations were associated with functional defects which were partially reverted through the use of lipid-lowering strategies. Implications of all the available evidence This study highlights the potential role of an altered cellular lipid metabolism in immunosenescence, providing clues to understand the epidemiological profile of emerging infections or tumors and to develop preventive and therapeutic strategies based on metabolic manipulation.