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Efficient T cell responses require the firm adhesion of T cells to their targets, e.g., virus-infected cells, which depends on T cell receptor (TCR)-mediated activation of β 2 -integrins. Gα s -coupled receptor agonists are known to have immunosuppressive effects, but their impact on TCR-mediated integrin activation is unknown. Using multimers of peptide major histocompatibility complex molecules (pMHC) and of ICAM-1-the ligand of β 2 -integrins-we show that the Gα s -coupled receptor agonists isoproterenol, epinephrine, norepinephrine, prostaglandin (PG) E 2 , PGD 2 , and adenosine strongly inhibit integrin activation on human CMV- and EBV-specific CD8 + T cells in a dose-dependent manner. In contrast, sleep, a natural condition of low levels of Gα s -coupled receptor agonists, up-regulates integrin activation compared with nocturnal wakefulness, a mechanism possibly underlying some of the immune-supportive effects of sleep. The findings are also relevant for several pathologies associated with increased levels of Gα s -coupled receptor agonists (e.g., tumor growth, malaria, hypoxia, stress, and sleep disturbances)., (© 2019 Dimitrov et al.)