| First Author | Bhadra R | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 6 | Pages | 2441-55 |
| PubMed ID | 24762437 | Mgi Jnum | J:212827 |
| Mgi Id | MGI:5582328 | Doi | 10.1172/JCI70522 |
| Citation | Bhadra R, et al. (2014) Intrinsic TGF-beta signaling promotes age-dependent CD8+ T cell polyfunctionality attrition. J Clin Invest 124(6):2441-55 |
| abstractText | 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-beta1. Furthermore, TGF-beta 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-beta signaling in CD8+ T cells was sufficient to rescue polyfunctionality in aged animals. Together, these data demonstrate that low levels of TGF-beta1 promote apoptosis of CD8+ effector T cells and high TGF-beta1 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-beta levels are observed in the elderly human population and in aged Drosophila, suggesting that TGF-beta represents an evolutionarily conserved negative regulator of the immune response in aging organisms. |
