Divergent effects of norepinephrine, dopamine and substance P on the activation, differentiation and effector functions of human cytotoxic T lymphocytes

Background: Neurotransmitters are important regulators of the immune system, with very distinct and varying effects on different leukocyte subsets. So far little is known about the impact of signals mediated by neurotransmitters on the function of CD8(+) T lymphocytes. Therefore, we investigated the influence of norepinephrine, dopamine and substance P on the key tasks of CD8(+) T lymphocytes: activation, migration, extravasation and cytotoxicity. Results: The activation of naive CD8(+) T lymphocytes by CD3/CD28 cross-linking was inhibited by norepinephrine and dopamine, which was caused by a downregulation of interleukin (IL)-2 expression via Erk1/2 and NF-kappa B inhibition. Furthermore, all of the investigated neurotransmitters increased the spontaneous migratory activity of naive CD8(+) T lymphocytes with dopamine being the strongest inducer. In contrast, activated CD8(+) T lymphocytes showed a reduced migratory activity in the presence of norepinephrine and substance P. With regard to extravasation we found norepinephrine to induce adhesion of activated CD8(+) T cells: norepinephrine increased the interleukin-8 release from endothelium, which in turn had effect on the activated CXCR1(+) CD8(+) T cells. At last, release of cytotoxic granules from activated cells in response to CD3 cross-linking was not influenced by any of the investigated neurotransmitters, as we have analyzed by measuring the beta-hexosamidase release. Conclusion: Neurotransmitters are specific modulators of CD8(+) T lymphocytes not by inducing any new functions, but by fine-tuning their key tasks. The effect can be either stimulatory or suppressive depending on the activation status of the cells.