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IL-15 Drives Metabolic Remodeling and Survival in Aged Immune Cells

Kylie Quinn

RMIT University, Bundoora, Australia

CD8 T cells are a critical immune mechanism for control of infections and cancer. They are activated by a specific antigen to proliferate and then kill infected or cancerous cells expressing that antigen. There are three main types of CD8 T cell: true naïve (TN) cells that have not encountered antigen, true memory (TMEM) cells that have encountered antigen, and virtual memory (TVM) cells, which have not encountered antigen but have undergone semi-differentiation in response to inflammation-associated cytokines. Of note, a metabolic phenotype known as high spare respiratory capacity (SRC) is thought to promote both CD8 T cell activation and survival. Given that CD8 T cell immune responses decline substantially with age and TVM cells, in particular, become refractory to activation with age, we first hypothesised that age-related dysfunction in TVM cells was driven by a loss of metabolic capacity and SRC. Instead, we found that SRC was already high in young TVM cells, as compared to TN and TMEM cells, and SRC increased substantially in TVM cells with age. This illustrated that high SRC did not necessarily augment CD8 T cell activation but we noted that high SRC did correlate with preferential survival of TVM cells. We then hypothesised that high SRC and increased survival were both driven by signaling from the inflammation-associated cytokine, IL-15. When we assessed IL-15 receptor expression, IL-15 signaling strength and expression of Bcl-2, an anti-apoptotic protein downstream of IL-15, all of these parameters were high in young TVM cells and increased further with age. Recent infection increased SRC in TVM cells but blockade of IL-15 lead to a decrease in SRC in TVM cells. Our study therefore suggests that high SRC in TVM cells is driven by IL-15, it is augmented by age-related inflammation and it promotes preferential survival of TVM cells with age.