The β1-adrenergic receptor links sympathetic nerves to T cell exhaustion

The β1-adrenergic receptor links sympathetic nerves to T cell exhaustion

Abstract
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 exhaustion1. 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 β1-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 β1-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 patients2,3, 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.



https://www.nature.com/articles/s41586-023-06568-6

 

From Dr Eric Topol:

“New @Nature

Important discovery linking the β-receptor, sympathetic nervous system, with T cell exhaustion, that has implications for #LongCovid, POTS, post-viral syndromes & various cancers (by blocking β signaling)”

https://twitter.com/user/status/1704518468970877213

 

I suspect this paper will end up highly cited.