Intrinsic TGF-β signaling promotes age-dependent CD8+ T cell polyfunctionality attrition.
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.
Rajarshi
R
Bhadra
Magali M
MM
Moretto
Julio C
JC
Castillo
Constantinos
C
Petrovas
Sara
S
Ferrando-Martinez
Upasana
U
Shokal
Manuel
M
Leal
Richard A
RA
Koup
Ioannis
I
Eleftherianos
Imtiaz A
IA
Khan
D000368:Aged; D000375:Aging / Q000276:immunology* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000145:classification / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D004331:Drosophila melanogaster / Q000235:genetics / Q000276:immunology; D009670:Encephalitozoon cuniculi / Q000276:immunology / Q000472:pathogenicity; D005260:Female; D006801:Humans; D037181:Lectins, C-Type; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D018448:Models, Immunological; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000276:immunology*
D016827:CD8 Antigens; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D053773:Transforming Growth Factor beta1