CD4 T cells differentially express cellular machinery for serotonin signaling, synthesis, and metabolism

CD4 T cells play a major role to orchestrate the immune response. Upon activation, CD4 T cells differentiate into effector T cell (Teff) or regulatory T cell (Treg) subsets that promote or suppress the immune response, respectively. Along with these unique immunological roles, CD4 T cell subsets have specific metabolic requirements and programs that can influence the immune response. We therefore examined the metabolite levels of Teff and Treg in detail. Surprisingly, the metabolite showing the largest difference between Teff and Treg was serotonin (5-HT), revealing a potentially distinct role for serotonin in CD4 T cell function. 5-HT is well known as a neurotransmitter and recently has been recognized to play a role in the immune response; however, little is known about the immune cell type-specific expression of the serotonergic machinery and receptors. We therefore examined the serotonergic-related machinery in Teff and Treg and found differential expression of the serotonin transporter SERT and 5-HT1a and 5-HT2 receptors. We also found that Treg express tryptophan hydroxylase, which converts tryptophan to serotonin, suggesting for the first time that Treg synthesize serotonin. Our results in this study expand the potential immunomodulatory role of serotonin in CD4 T cell biology and could ultimately aid the development of novel immunomodulatory targets for treatment of autoimmune and neuropsychiatric disorders.