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Intrinsic TGF-β signaling promotes age-dependent CD8+ T cell polyfunctionality attrition
Rajarshi Bhadra, … , Ioannis Eleftherianos, Imtiaz A. Khan
Rajarshi Bhadra, … , Ioannis Eleftherianos, Imtiaz A. Khan
Published April 24, 2014
Citation Information: J Clin Invest. 2014;124(6):2441-2455. https://doi.org/10.1172/JCI70522.
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Research Article Immunology Article has an altmetric score of 25

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

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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

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Figure 4

Plasma TGF-β1 is highly elevated in E. cuniculi–challenged aged mice.

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Plasma TGF-β1 is highly elevated in E. cuniculi–challenged aged mice.
(A...
(A) TGF-β1 plasma levels in parasite-infected mice of various ages at day 12 after infection. (B) TGF-β plasma levels in E. cuniculi–challenged young majority and aged majority BM chimeras generated in young or aged recipients. (C) Plasma collected from young (6–8 weeks old) or aged (14–15 months old) mice treated with PBS, with anti-CD25, or with anti-thymocyte to deplete T cells was assayed for TGF-β. (D and E) TGF-βRII expression was measured on splenic CD8+ subsets in young (6–8 weeks old) and aged (14–15 months old) mice by polychromatic flow cytometry. (F and G) Direct ex vivo SMAD2/3 phosphorylation on splenic CD8+ subsets. (H and I) Young (CD90.1; 6–8 weeks old) and aged (CD90.2; 14 months old) CD8+ T cells from naive donors were adoptively transferred into young Cd8–/– recipients, followed by parasite challenge. TGF-βRII expression was evaluated in the recipients on donor effector CD8+KLRG1+ T cells in spleen. (J) TGF-βRII expression levels on splenic effector CD8+KLRG1+ T cells in young majority or aged majority BM chimeras formed in young or aged recipients. Y, young; A, aged. Data represent 2 experiments with 4 mice per group. Numbers in histograms denote MFI.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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