Nerve‐Driven Immunity: The Direct Effects of Neurotransmitters on T‐Cell Function

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Abstract
Abstract: 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 non‐peptidergic 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.