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

Anna-Maria Globig, Steven Zhao, Jessica Roginsky, Vivien I. Maltez, Juan Guiza, Natalia Avina-Ochoa, Maximilian Heeg, Filipe Araujo Hoffmann, Omkar Chaudhary, Jiawei Wang, Gokhan Senturk, Dan Chen, Carolyn O’Connor, Samuel Pfaff, Ronald N. Germain, Kurt A. Schalper, Brinda Emu and Susan M. Kaech ()
Additional contact information
Anna-Maria Globig: Salk Institute for Biological Studies
Steven Zhao: Salk Institute for Biological Studies
Jessica Roginsky: Salk Institute for Biological Studies
Vivien I. Maltez: Laboratory of Immune System Biology, NIAID, NIH
Juan Guiza: Yale School of Medicine
Natalia Avina-Ochoa: Salk Institute for Biological Studies
Maximilian Heeg: University of California San Diego
Filipe Araujo Hoffmann: Salk Institute for Biological Studies
Omkar Chaudhary: Yale School of Medicine
Jiawei Wang: Yale School of Medicine
Gokhan Senturk: Salk Institute for Biological Studies
Dan Chen: Salk Institute for Biological Studies
Carolyn O’Connor: Salk Institute for Biological Studies
Samuel Pfaff: Salk Institute for Biological Studies
Ronald N. Germain: Laboratory of Immune System Biology, NIAID, NIH
Kurt A. Schalper: Yale School of Medicine
Brinda Emu: Yale School of Medicine
Susan M. Kaech: Salk Institute for Biological Studies

Nature, 2023, vol. 622, issue 7982, 383-392

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06568-6

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