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Instructor/Advisor

Dr. Leena Bharath

Keywords

Aging, Cytokines, T cells

Abstract

Aging promotes numerous intracellular changes in CD4 + T cells that impact their effector function. Our prior work showed that T cells from older(O) adults had higher expression and activity of mitochondrial complex II (Succinate dehydrogenase (SDH)). T cells from O adults also produced higher levels of cytokines that are generally considered proinflammatory, such as Th17 cytokines, IL-17A/F, and Th-17 supportive cytokines TNFα and IL-6 compared to T cells from young(Y) adults.

Aim: The objective of our study is to evaluate if hyperactivation of SDH is required for the induction of proinflammatory cytokines and the mechanistic link between SDH and Th17 cytokine production.

Methods: CD4 + T cells were isolated from lean normoglycemic young (Y; avg: 31.81 yrs; BMI 22.20 kg/m 2) and older (O; avg: 68.11 yrs; BMI 23.46 kg/m 2) adults. SDH was pharmacologically and genetically modulated, and cellular signaling and cytokine production were assessed.

Results: Our data shows that SDH activation induces rapid oxidation of succinate and disrupts the ratio of succinate: α-Ketoglutarate and succinate: fumarate, which impacts redox signaling and promotes a Th17 proinflammatory phenotype. Genetic and pharmacological inhibition of SDH in T cells from O adults prevents proinflammatory cytokine production, whereas pharmacological activation of SDH in T cells from Y adults recapitulated the proinflammatory Th-17 profiles observed in T cells from O adults, thus establishing a mechanistic link between SDH and Th17 inflammation.

Succinate Regulates Age-Associated T Cell Inflammation

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