Immune cells rely on cell-cell communication to specify and fine-tune their responses. They express an extensive network of cell communication modes, including a vast repertoire of cell surface and transmembrane receptors and ligands, membrane vesicles, junctions, ligand and voltage-gated ion channels, and transporters. During a crosstalk between the nervous system and the immune system these modes of cellular communication and the downstream signal transduction events are influenced by neurotransmitters present in the local tissue environments in an autocrine or paracrine fashion. Neurotransmitters thus influence innate and adaptive immune responses. In addition, immune cells send signals to the brain through cytokines, and are present in the brain to influence neural responses. Altered communication between the nervous and immune systems is emerging as a common feature in neurodegenerative and immunopathological diseases. Here, we present the mechanistic frameworks of immunostimulatory and immunosuppressive effects critical neurotransmitters-dopamine (3,4-dihydroxyphenethylamine), serotonin (5hydroxytryptamine), substance P (trifluoroacetate salt powder), and L-glutamateexert on lymphocytes and non-lymphoid immune cells. Furthermore, we discuss the possible roles neurotransmitter-driven neuroimmune networks play in the pathogenesis of neurodegenerative disorders, autoimmune diseases, cancer, and outline potential clinical implications of balancing neuroimmune crosstalk by therapeutic modulation.
The interaction between the nervous system and immune system has sparked interest in recent years. Emerging evidence shows an intricate neuro-immune network. Studies revealed that neurotransmitters can trigger immune cell responses such as cytokine secretion, integrin expression, and chemotaxis. We were intrigued by the expression of various neurotransmitter receptors on mouse T lymphocytes. Specifically, following TCR stimulation, glutamate receptors (GluR) were significantly upregulated on both CD4+ and CD8+T cells, with a peak at 48 h. Concomitant with the upregulation of activation molecules CD69, CD25 and CD44, proliferating CD8+T cells presented higher levels of GluR3 and GluR1 when compared with non-proliferating cells, as well as a higher production of IFN-g and granzyme B. Based on the augmentation of GluR expression upon T cell activation, we evaluated the role of GluR signaling in modulating T cells in orthotopic mammary tumors that express a low avidity epitope of a model antigen hemagglutinin (4T1HA). We found that HA-reactive CD8+ T cells in the tumor-infiltrate had an upregulated expression of GluR3 and GluR1 when compared with control group. The blockade of GluR signaling down-regulated expression of CD69 and CD25, impaired T cell proliferation, and interfered with their cytolytic activity. Early TCR-activation pathways such as Lck/Akt as well as calcium signaling were affected by GluR antagonists, suggesting their signaling interaction. Overall, data suggest that glutamate receptors may have costimulatory effects on T cell activation and glutamate agonists may boost T cell response in an immunosuppressive setting such as cancer.
The nervous system can regulate the exacerbation of pro-inflammatory immune response predominantly in an immunosuppressive setting. Studies also suggest that glutamate, serotonin, dopamine, and substance P trigger immune responses such as cytokine secretion, integrin expression, and chemotaxis. We evaluated the role of neurotransmitters in modulating and/or activating T cells in mouse tumor models of kidney (RencaHA) and breast cancers (4T1HA) expressing viral hemagglutinin as a defined immunodominant antigen. We observed an expression of glutamate receptors GluR1, GluR3, GluR5, NMDA1 and NMDA2B as well as dopamine receptor DRD3, substance P receptor NK1, serotonin receptors 5HT7, and 5HT2B on mouse T lymphocytes. In particular, concomitant with the upregulation of T cell activation molecules CD25 and CD44, we found that both CD4 + and CD8 + T cells significantly upregulated expression of glutamate receptors (GluRs) following TCR stimulation, with CD8 + T cells maintaining a higher receptor expression for a longer time than that on CD4 + T cells. In mice bearing RencaHA and 4T1HA tumors also, HAreactive CD8 + T cells in the tumor-draining LN and tumor-infiltrating lymphocytes showed an upregulated expression of GluR3 and GluR1 receptors. Moreover, proliferating CD8 + T cells presented higher levels of GluR3 and GluR1 when compared with non-proliferating T cells. We are currently investigating the dynamics of glutamate receptor signaling on various intracellular components of T cell activation signaling as well as cytokine expression, survival, and cytolytic function in the presence of glutamate receptor agonists and antagonists. Further, we observed that the expression of glutamate receptors could be modulated by cancer therapeutic proteasome inhibitor drug bortezomib concomitant with the expression of intracellular TCR signaling molecule CD3zeta and IFN-gamma in mice bearing RencaHA and 4T1HA tumors. Thus, pharmacological modulation of glutamate receptor signaling could be a novel strategy for enhancing anti-tumor immunity of T cells by overcoming tumorinduced immunosuppression, most likely by increasing T cell survival and cytolytic function. These findings shed new insights on unexplored neural-immune cross-talk mechanisms to overcome tumor immunosuppression and enhance anti-tumor T cell function with a potential to improve T cell immunotherapy of solid cancers.
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