Remote control of T cell exhaustion by muscle
Virology
Final Report Abstract
We made progress in understanding the role of muscle in regulating T cell exhaustion. Chronic viral infections and cancers frequently cause unwilling loss of body weight and muscle atrophy, also known as cachexia. It remains incompletely understood if and how the reduction of muscle influences antiviral and anti-tumor immune cells (such as CD8+ T cell) metabolism, intracellular signaling, and effector functions. Using mouse models with germ-line deficiency of IL-15 or muscle-specific ablation of IL-15, we observed that muscle-derived IL-15 plays an essential role in antagonizing CD8+ T cell exhaustion. Funded by this DFG grant, we have 1) found that muscle-derived IL-15 inhibited CD8+ T cell exhaustion, 2) discovered that muscle-derived IL-15 promoted CD8+ T cell survival and proliferation, 3) found increasing muscle mass elevated IL-15 protein levels, and protected against T cell exhaustion during chronic infection. These results highlight muscle as an important remote regulator of antiviral T cell exhaustion. Partially inspired by these research results, I applied for other third-party funding and received an ERC Consolidator Award in 2022.
