Serotonin Degradation and Lipid Metabolism Regulate Human Tc2 Cell Effector Functions

ABSTRACT Background Cytotoxic type 2 T cells (Tc2) are increasingly recognized as contributors to type 2 inflammation, including asthma, yet the metabolic programs that support their function remain poorly defined. We aimed to define the metabolic requirements of Tc2 cells, identify pathways that regulate their effector function, and assess whether serotonin‐modifying therapies are associated with altered Tc2 responses and allergic sensitization in humans. Methods Tc2 cells from human peripheral blood and lung tissue were analyzed using Seahorse metabolic assays, Mitotracker staining, flow cytometry, and RNA sequencing. Effector functions were evaluated following inhibition of glycolysis, fatty acid metabolism, and monoamine oxidase A (MAOA) inhibition. In parallel, anti‐depressant prescription data were analyzed in the population‐based BAMSE cohort to assess associations with allergic sensitization. Peripheral blood mononuclear cells from individuals prescribed selective serotonin reuptake inhibitors (SSRIs) and matched controls were stimulated ex vivo to assess cytokine production. Results Tc2 cells exhibited a distinct metabolic profile characterized by increased mitochondrial respiration, glycolytic activity, and elevated expression of GLUT1 and CD36. Type 2 cytokine production (IL‐4, IL‐5, IL‐13) was enhanced by alarmins and significantly reduced following inhibition of glycolysis, fatty acid metabolism, or PPARγ activity. RNA sequencing identified high MAOA expression in Tc2 cells, and pharmacological inhibition of MAOA selectively reduced type 2 cytokine production without affecting IFN‐γ. In the BAMSE cohort, dispensing of prescribed anti‐depressive drugs was associated with reduced IgE sensitization. Consistent with these findings, individuals prescribed SSRIs exhibited reduced IL‐5 + and IL‐13 + expressing Tc2 cells and increased IFN‐γ–producing Tc2 cells following ex vivo stimulation. Conclusion Tc2 cells rely on coordinated lipid metabolism and serotonin catabolism to sustain type 2 cytokine production. Serotonin‐modifying therapies were associated with reduced allergic sensitization and altered Tc2 function in humans, consistent with a link between serotonin signaling and type 2 immunity.