title: Increased T-bet is associated with senescence of influenza virus-specific CD8 T cells in aged humans.
abstract: Aged individuals have increased morbidity and mortality following influenza and other viral infections, despite previous exposure or vaccination. Mouse and human studies suggest increased senescence and/or exhaustion of influenza virus-specific CD8 T cells with advanced age. However, neither the relationship between senescence and exhaustion nor the underlying transcriptional pathways leading to decreased function of influenza virus-specific cellular immunity in elderly humans are well-defined. Here, we demonstrate that increased percentages of CD8 T cells from aged individuals express CD57 and KLRG1, along with PD-1 and other inhibitory receptors, markers of senescence, or exhaustion, respectively. Expression of T-box transcription factors, T-bet and Eomes, were also increased in CD8 T cells from aged subjects and correlated closely with expression of CD57 and KLRG1. Influenza virus-specific CD8 T cells from aged individuals exhibited decreased functionality with corresponding increases in CD57, KLRG1, and T-bet, a molecular regulator of terminal differentiation. However, in contrast to total CD8 T cells, influenza virus-specific CD8 T cells had altered expression of inhibitory receptors, including lower PD-1, in aged compared with young subjects. Thus, our data suggest a prominent role for senescence and/or terminal differentiation for influenza virus-specific CD8 T cells in elderly subjects.
authors: Institute for Immunology, Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors: Douglas V
authors: DV
authors: Dolfi
authors: Kathleen D
authors: KD
authors: Mansfield
authors: Antonio M
authors: AM
authors: Polley
authors: Susan A
authors: SA
authors: Doyle
authors: Gordon J
authors: GJ
authors: Freeman
authors: Hanspeter
authors: H
authors: Pircher
authors: Kenneth E
authors: KE
authors: Schmader
authors: E John
authors: EJ
authors: Wherry
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016922:Cellular Senescence / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007251:Influenza, Human / Q000276:immunology* / Q000378:metabolism; D008297:Male; D020825:T-Box Domain Proteins / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult; D000098815:T-bet Transcription Factor
chemical_list: D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor
keywords: CD107; CD57; Eomes; KLRG-1; PD-1; exhaustion