Regulation of Natural Killer Cell Functions by Catecholamines

• Applicants: Professorin Dr. Silvia Capellino; Professor Dr. Carsten Watzl
• Subject Area: Immunology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442103981

There is good evidence that psychological stress is associated with higher incidence of infectious diseases and cancer, suggesting that stress has an impact on the function of the immune system. The presence of neurotransmitter receptors on immune cells enables a direct influence of the nervous system on the immune response. However, the molecular details of this interplay between psychological stress and immune cells are poorly understood. Psychological stress results in the activation of the sympathetic nervous system, leading to the release of catecholamines such as norepinephrine and dopamine. Natural Killer (NK) cells express receptors for catecholamines and the activity of these innate lymphocytes is important for early and effective immune reactions against infected and transformed cells. Therefore, we hypothesize that psychological stress influences the activity of NK cells via the sympathetic nervous system. Our preliminary results show that acute exposure of NK cells to epinephrine or dopamine can inhibit NK cell cytotoxicity and cytokine production. Additionally, epinephrine can effectively block inside-out signals which are necessary for the induction of high binding activity of the integrin LFA-1 on NK cells. Interestingly, chronic exposure to epinephrine can lead to desensitization of this response, which may be a model system to investigate the differences between acute and chronic stress on the immune system. Taken together, these preliminary results confirm a crucial role of catecholamines in modulating NK cell functions.The aim of our project is to perform a detailed analysis of the effects of catecholamines on NK cell functions. We will investigate the signaling pathways that are involved in the effects of epinephrine and dopamine on NK cells. Our planned experiments will further determine the molecular details of how catecholamines affect NK cell functions such as integrin activity, cytokine production, cytotoxicity, and metabolism. We will use chronic exposure of NK cells to catecholamines as a model to study the effect of chronic stress on NK cells. In addition to biochemical approaches, we will also utilize unbiased expression analysis by RNAseq and proteome analysis to determine the changes induced upon chronic exposure to catecholamines. These studies will provide a novel and important insight into the molecular details of how acute and chronic stress affects the function of NK cells. This will be essential for defining biomarkers for the effect of stress on humans in real life situations.

• DFG Programme: Research Grants