Nerve-driven immunity: The direct effects of neurotransmitters on T-cell function

We carried out studies to explore whether neurotransmitters can directly interact with their T-cell-expressed receptors, leading to either activation or suppression of various T-cell functions. Human and mouse T cells were thus exposed directly to neurotransmitters in the absence of any additional molecule, and various functions were studied, among them cytokine secretion, proliferation, and integrin-mediated adhesion and migration. In this review, I describe the effects of four neuropeptides: somatostatin (SOM), calcitonin-gene-related-peptide (CGRP), neuropeptide Y (NPY), and substance P (Sub P), and one nonpeptidergic neurotransmitter - dopamine. We found that SOM, NPY, CGRP, and dopamine interact directly with T cells, leading to the activation of β₁ integrins and to the subsequent integrin-mediated T-cell adhesion to a component of the extracellular matrix. In contrast, Sub P had a reverse effect - full blockage of integrin-mediated T-cell adhesion triggered by a variety of signals. Each of these neurotransmitters exerted its effect through direct interaction with its specific receptor on the T-cell surface, since the effect was fully blocked by the respective receptor-antagonist. Taken together, this set of findings indicates that neurotransmitters can directly interact with T cells and provide them with either positive (integrin-activating, pro-adhesive) or negative (integrin-inhibiting, anti-adhesive) signals. We further found that the above neurotransmitters, by direct interaction with their specific receptors, drove T cells (of the Th0, Th1, and Th2 phenotypes) into the secretion of both typical and atypical ('forbidden') cytokines. These results suggested that neurotransmitters can substantially affect various cytokine-dependent T-cell activities. As a whole, our studies suggest an important and yet unrecognized role for neurotransmitters in directly dictating or modulating numerous T-cell functions under physiological and pathological conditions.