<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Aging- and obesity-associated metabolic reprogramming suppresses CD8+ T cell responses"^^ . "Aging and obesity are growing global health issues and are associated with increased susceptibility towards infectious diseases, increased cancer risk and decreased vaccination efficacy. CD8+ T cells are the main effectors of cell-mediated adaptive immunity and form antigen-specific memory after pathogen clearance. However, upon antigen persistence during cancer or chronic infections, T cells become dysfunctional, a state termed T cell exhaustion. In CD8+ T cells, the transcription factor T cell factor 1 (TCF1, encoded by Tcf7) is a stemness marker and high expression is associated with CD8+ T cell longevity and superior functionality. The aim of this study was to identify synergistic effects of aging and obesity on the CD8+ T cell phenotype and function as well as on the plasma metabolite profile to ultimately find a causal relation.\r\nA diet-induced obesity mouse model of young and aged mice was used to study the effect of aging and obesity on the CD8+ T cell phenotype as well as on the plasma metabolite profile. Flow cytometric analysis of naïve CD8+ T cells revealed a terminally differentiated, exhausted CD8+ T cell phenotype with reduced TCF1 expression in aged obese compared to young lean mice. Mass spectrometric analysis of plasma samples identified the tryptophan metabolite 3-Indolepropionic acid (3-IPA) to be synergistically decreased by aging and obesity. Treatment of primary murine and human CD8+ T cells with 3-IPA in therapeutic concentrations, increased TCF1 expression as well as other stemness markers and reversed T cell exhaustion in vitro. Using the lymphocytic choriomeningitis virus (LCMV) infection model, 3-IPA pre-treatment of antigen-specific CD8+ T cells rescued aging- and obesity-impaired anti-viral CD8+ T cell effector and memory functions.\r\nTo elucidate the molecular mechanism how 3-IPA increases CD8+ T cell stemness, a pull-down experiment was performed and γ-catenin was identified as a 3-IPA-binding protein. Further investigations revealed decelerated degradation of γ-catenin and its close homologue β-catenin upon 3-IPA treatment in activated CD8+ T cells. Moreover, 3-IPA treatment increased Tcf7 promoter activity in a luciferase assay, while the role of β- and γ-catenin in this context remains elusive.\r\nIn summary, aging and obesity synergistically decreased stemness, recall capacity and anti-viral effector functions of CD8+ T cells, thus making them a detrimental combination. Treatment of CD8+ T cells with 3-IPA restored those defects, suggesting a therapeutic potential of 3-IPA to overcome aging- and obesity-mediated CD8+ T cell dysfunctionality."^^ . "2024" . . . . . . . "Alessa"^^ . "Mieg"^^ . "Alessa Mieg"^^ . . . . . . "Aging- and obesity-associated metabolic reprogramming suppresses CD8+ T cell responses (PDF)"^^ . . . "Thesis Alessa Mieg.pdf"^^ . . . "Aging- and obesity-associated metabolic reprogramming suppresses CD8+ T cell responses (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Aging- and obesity-associated metabolic reprogramming suppresses CD8+ T cell responses (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Aging- and obesity-associated metabolic reprogramming suppresses CD8+ T cell responses (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Aging- and obesity-associated metabolic reprogramming suppresses CD8+ T cell responses (Other)"^^ . . . . . . "small.jpg"^^ . . . "Aging- and obesity-associated metabolic reprogramming suppresses CD8+ T cell responses (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #32639 \n\nAging- and obesity-associated metabolic reprogramming suppresses CD8+ T cell responses\n\n" . "text/html" . .