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

[EndME]

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

 

[cassava7]

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)”

 

[SNT Gatchaman]

T cell exhaustion is a specific CD8+ T cell differentiation state that is induced by chronic exposure to antigen such as from chronic viral infections or cancer. This state is characterized by the progressive loss of effector functions and the expression of multiple inhibitory receptors

In recent years, several subsets of TOX+ exhausted CD8+ T cells (TEX) have been defined, leading to the establishment of a progenitor-progeny lineage relationship with progressive development of exhaustion. In this paradigm, TOX+ progenitors of exhausted T cells (TEXprog , PD-1+ SLAMF6+ TCF1+), which exhibit stem-cell-like properties, sustain the T cell response by proliferating to self-renew and producing more terminally differentiated effectors

Activation of the sympathetic nervous system also influences the immune system, including T helper cell differentiation and CD8+ T cell responses to infection and tumours by altering priming and migration. Catecholamines achieve these effects by signalling through α-adrenergic receptors and the β-adrenergic receptors ADRB1, ADRB2 and ADRB3. Despite the documented expression of adrenergic receptors on T cells, the regulation of T cell responses by the sympathetic nervous system has frequently been ascribed to indirect mechanisms, for example, through the induction of noradrenaline-mediated hypoxia or the modulation of other immune cell populations.

Tissues including primary and secondary lymphoid organs are densely innervated by the sympathetic nervous system with direct interactions of nerve fibres and splenocytes [...] led us to propose that the endogenous stress response can directly regulate T cell differentiation and function during immune responses. Here we show that catecholamines contribute to the progression of CD8+ T cell exhaustion in chronic viral infection and cancer through the β1-adrenergic receptor ADRB1.

we conclude that ADRB1 expression is a conserved and targetable feature of T cell exhaustion across different aetiologies, tumour types and species.

This could explain why concurrent use of ADRB1-selective β-blockers with adjuvant ICB (pembrolizumab) was associated with improved recurrence-free survival in patients with melanoma in a recent large clinical trial

Our findings provide a new framework for the regulation of antiviral and anti-tumour T cell responses by the sympathetic nervous system and support further investigation into targeted manipulation of adrenergic receptors in combination with ICB [immune checkpoint blockade] as a potential means to induce effective anti-tumour T cell responses.

I suspect this paper will end up highly cited.