UCSF

One of the consequences of human aging is an overall decline in immune function. A hallmark of this aging process, termed immunosenescence, is the downregulation of co-receptor CD28 from the surface of CD8+ T cells. This population of terminally differentiated CD8+CD28– T cells accumulates during aging and chronic infections, and is linked to many age-related diseases observed in elderly individuals. In this thesis, we explore the molecular factors regulating CD8+CD28– T cell fate and function. In Chapter III, we find that resting CD8+CD28– T cells possess a unique glycolytic profile that is associated with their enhanced cytotoxicity and decreased expression of NAD+-dependent protein deacetylase SIRT1. Global gene–expression profiling identified the transcription factor FoxO1 as a SIRT1-target involved in the transcriptional reprogramming of CD8+CD28– T cells. FoxO1 is proteasomally degraded in CD8+CD28– T cells, and inhibiting its activity in CD8+CD28+ T cells recapitulates the metabolic and cytotoxic phenotype of resting CD8+CD28– T cells. In Chapter IV, we explore the signaling and functional consequences of IL-15, a pro-memory cytokine that serves as a TCR-independent activation signal for CD8+CD28– T cells. We find that IL-15 signals through mTOR to upregulate a metabolic program conducive for effector T cell function. Targeting CD8+CD28– T cells with a SIRT1 activator or glucose-starvation suppresses IL-15-induced cytotoxicity and proliferation. Altogether, this body of work identifies new molecular pathways that regulate the function of human CD8+CD28– T cells—providing deeper insight into the mechanisms of immune aging, as well as novel therapeutic opportunities to target it.