RT Journal Article SR Electronic T1 Functional and metabolic fitness of human CD4+ T lymphocytes during metabolic stress JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202101013 DO 10.26508/lsa.202101013 VO 4 IS 12 A1 Holthaus, Lisa A1 Sharma, Virag A1 Brandt, Daniel A1 Ziegler, Anette-Gabriele A1 Jastroch, Martin A1 Bonifacio, Ezio YR 2021 UL http://www.life-science-alliance.org/content/4/12/e202101013.abstract AB Human CD4+ T cells are essential mediators of immune responses. By altering the mitochondrial and metabolic states, we defined metabolic requirements of human CD4+ T cells for in vitro activation, expansion, and effector function. T-cell activation and proliferation were reduced by inhibiting oxidative phosphorylation, whereas early cytokine production was maintained by either OXPHOS or glycolytic activity. Glucose deprivation in the presence of mild mitochondrial stress markedly reduced all three T-cell functions, contrasting the exposure to resveratrol, an antioxidant and sirtuin-1 activator, which specifically inhibited cytokine production and T-cell proliferation, but not T-cell activation. Conditions that inhibited T-cell activation were associated with the down-regulation of 2′,5′-oligoadenylate synthetase genes via interferon response pathways. Our findings indicate that T-cell function is grossly impaired by stressors combined with nutrient deprivation, suggesting that correcting nutrient availability, metabolic stress, and/or the function of T cells in these conditions will improve the efficacy of T-cell–based therapies.