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Here, we study the effect of epinephrine\u2010mediated stimulation of the \u03b22\u2010adrenergic receptor (\u03b22AR) on the function of human NK cells. Epinephrine stimulation inhibited early NK cell signaling events and blocked the function of the integrin LFA\u20101. This reduced the adhesion of NK cells to ICAM\u20101, explaining how NK cells are mobilized into the peripheral blood upon epinephrine release during acute stress or exercise. Additionally, epinephrine stimulation transiently reduced NK cell degranulation, serial killing, and cytokine production and affected metabolic changes upon NK cell activation via the cAMP\u2010protein kinase A (PKA) pathway. Repeated exposure to \u03b22AR agonists resulted in the desensitization of the \u03b22AR via a PKA feedback loop\u2010initiated G\u2010protein switch. Therefore, acute epinephrine stimulation of chronically \u03b22AR stimulated NK cells no longer resulted in inhibited signaling and reduced LFA\u20101 activity. Sustained stimulation by long\u2010acting \u03b22\u2010agonists (LABA) not only inhibited NK cell functions but also resulted in desensitization of the \u03b22AR. However, peripheral NK cells from LABA\u2010treated asthma patients still reacted unchanged to epinephrine stimulation, demonstrating that local LABA administration does not result in detectable systemic effects on NK cells.<\/jats:p>","DOI":"10.1002\/eji.202451299","type":"journal-article","created":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T00:56:22Z","timestamp":1727744182000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Chronic stimulation desensitizes \u03b22\u2010adrenergic receptor responses in natural killer cells"],"prefix":"10.1002","volume":"54","author":[{"given":"Martin","family":"J\u00fcrgens","sequence":"first","affiliation":[{"name":"Department for Immunology Leibniz Research Centre for Working Environment and Human Factors (IfADo) at TU Dortmund  Dortmund 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