Intrinsic TGF-β signaling promotes age-dependent CD8⁺ T cell polyfunctionality attrition

• Text
• PDF

Abstract

Advanced age is associated with immune system deficits that result in an increased susceptibility to infectious diseases; however, specific mediators of age-dependent immune dysfunction have not been fully elucidated. Here we demonstrated that aged mice exhibit poor effector CD8⁺ T cell polyfunctionality, primarily due to CD8⁺ T cell–extrinsic deficits, and that reduced CD8⁺ T cell polyfunctionality correlates with increased susceptibility to pathogenic diseases. In aged animals challenged with the parasite Encephalitozoon cuniculi, effector CD8⁺ T cell survival and polyfunctionality were suppressed by highly elevated TGF-β1. Furthermore, TGF-β depletion reduced effector CD8⁺ T cell apoptosis in both young and aged mice and enhanced effector CD8⁺ T cell polyfunctionality in aged mice. Surprisingly, intrinsic blockade of TGF-β signaling in CD8⁺ T cells was sufficient to rescue polyfunctionality in aged animals. Together, these data demonstrate that low levels of TGF-β1 promote apoptosis of CD8⁺ effector T cells and high TGF-β1 levels associated with age result in both CD8⁺ T cell apoptosis and an altered transcriptional profile, which correlates with loss of polyfunctionality. Furthermore, elevated TGF-β levels are observed in the elderly human population and in aged Drosophila, suggesting that TGF-β represents an evolutionarily conserved negative regulator of the immune response in aging organisms.

Authors

Rajarshi Bhadra, Magali M. Moretto, Julio C. Castillo, Constantinos Petrovas, Sara Ferrando-Martinez, Upasana Shokal, Manuel Leal, Richard A. Koup, Ioannis Eleftherianos, Imtiaz A. Khan