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Abstract
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. A 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. To 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. In 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.
Document type: | Dissertation |
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Supervisor: | Cui, Dr. Guoliang |
Place of Publication: | Heidelberg |
Date of thesis defense: | 16 December 2022 |
Date Deposited: | 16 Feb 2023 12:54 |
Date: | 2024 |
Faculties / Institutes: | The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences |