Serotonin decreases the production of Th1/Th17 cytokines and elevates the frequency of regulatory CD4+ T‐cell subsets in multiple sclerosis patients

Excessive levels of proinflammatory cytokines in the CNS are associated with reduced serotonin (5‐HT) synthesis, a neurotransmitter with diverse immune effects. In this study, we evaluated the ability of exogenous 5‐HT to modulate the T‐cell behavior of patients with MS, a demyelinating autoimmune disease mediated by Th1 and Th17 cytokines. Here, 5‐HT attenuated, in vitro, T‐cell proliferation and Th1 and Th17 cytokines production in cell cultures from MS patients. Additionally, 5‐HT reduced IFN‐γ and IL‐17 release by CD8+ T cells. By contrast, 5‐HT increased IL‐10 production by CD4+ T cells from MS patients. A more accurate analysis of these IL‐10‐secreting CD4+ T cells revealed that 5‐HT favors the expansion of FoxP3+CD39+ regulatory T cells (Tregs) and type 1 regulatory T cells. Notably, this neurotransmitter also elevated the frequency of Treg17 cells, a novel regulatory T‐cell subset. The effect of 5‐HT in upregulating CD39+ Treg and Treg17 cells was inversely correlated with the number of active brain lesions. Finally, in addition to directly reducing cytokine production by purified Th1 and Th17 cells, 5‐HT enhanced in vitro Treg function. In summary, our data suggest that serotonin may play a protective role in the pathogenesis of MS. The serotonin (5‐HT), a neurotransmitter released by serotonergic neurons of CNS, reduces both T‐cell proliferation and Th1/Tc‐1 and Th17/Tc‐1‐related cytokine production by cell cultures from MS patients. Further, in system, serotonin upregulates not only the frequency of different Treg subsets but also enhances Treg function.