The β-adrenergic Receptor Links Sympathetic Nerves to T cell Exhaustion

CD8 T cells are essential components of the immune response against viral infections and tumours, and are capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion. Although it is clear that chronic antigen contributes to CD8 T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a new link between the stress-associated catecholamines and the progression of T cell exhaustion through the β-adrenergic receptor ADRB1. We identify that exhausted CD8 T cells increase ADRB1 expression and that exposure of ADRB1 T cells to catecholamines suppresses their cytokine production and proliferation. Exhausted CD8 T cells cluster around sympathetic nerves in an ADRB1-dependent manner. Ablation of β-adrenergic signalling limits the progression of T cells towards the exhausted state in chronic infection and improves effector functions when combined with immune checkpoint blockade (ICB) in melanoma. In a pancreatic cancer model resistant to ICB, β-blockers and ICB synergize to boost CD8 T cell responses and induce the development of tissue-resident memory-like T cells. Malignant disease is associated with increased catecholamine levels in patients, and our results establish a connection between the sympathetic stress response, tissue innervation and T cell exhaustion. Here, we uncover a new mechanism by which blocking β-adrenergic signalling in CD8 T cells rejuvenates anti-tumour functions.