Immunosenescence, the age-associated decline in immunity, leads to increased susceptibility to infection and reduced vaccine efficacies. Most influenza-associated deaths in industrial countries occur among the elderly. Chronic viral infection and age-associated inflammation are known to promote immunosenescence. Immunosenescence of CD8 T cells is characterized by reduced response to immune stimuli, increased terminal differentiation, and elevated expression of co-inhibitor receptors. In contrast, T cells with stem cell-like characteristics survive decades after vaccination and exhibit superior therapeutic effects in immunotherapies. In mice chronically infected by lymphocytic choriomeningitis virus (LCMV), I have identified antiviral CD8 T cells expressing high levels of transcription factor TCF1, which resemble stem cells and can both self-renew and replenish the more terminally differentiated TCF1low CD8 T cells. Moreover, stem cell-like CD8 T cells are critical for long-lasting CD8 T cell response against chronic LCMV infection and provide better protection against re-infection. Thus, Stem cell-like CD8 T cells are ideal targets for developing improved vaccines and immunotherapies against infection in the elderly. However, aging is associated with increased inflammation. Whether age-associated inflammation influences the differentiation of stem cell-like CD8 T cells is unclear. My preliminary data suggest that upon stimulation aged CD8 T cells are more prone to terminal differentiation and exhibits elevated activation of STAT3, a transcription factor that mediates the signaling of several inflammatory cytokines. I have also found evidence that inflammatory cytokine IL-21, STAT3, and Sestrin3 are potential regulators of stem cell-like CD8 T cell differentiation. Thus, I hypothesize that age-associated inflammatory cytokine signaling mediated by STAT3 inhibits the differentiation of stem cell-like CD8 T cells in aged mice by regulating Sestrin3 expression, and can be targeted to rejuvenate aged T cell immunity. In this study, I will use my newly developed in vitro culture system and mouse chronic LCMV infection model, and employ cutting- edge transcriptomic, epigenomic, and gene editing methods to study how aging and inflammation affect the differentiation of stem cell-like CD8 T cells. The results from this study will unveil how age-related inflammatory cytokine pathways regulate the differentiation of stem cell-like CD8 T cells during aging, and facilitate the development of new therapeutic strategies aiming to rejuvenate aged T cell immunity by enhancing stem cell- like CD8 T cell differentiation. My long-term goal is to lead a research group focusing on how to harness T cells to prevent and treat infectious diseases in the elderly. The K99/R00 mechanism will provide me the training, time and resource to gain a sound foothold in the field of immunosenescence and learn new skills through getting expert guidance as well as attending courses, seminars and conferences. !
The decline of immunity in the elderly leads to increased susceptibility to infections and loss of vaccine efficacy, which is an enormous challenge to the public health system. The goal of this study is to determine how age-associated increase in inflammation affects the differentiation of stem cell-like CD8 T cells, a subset of T lymphocytes that mediates long-lived immunity against infection. The outcomes of this study will provide key implication for developing improved vaccines and immunotherapies for the elderly. !