Copper homeostasis is critical for T cell activation

Abstract

Abstract Elevated copper levels are associated with autoimmune disease, infection, and tumors in both humans and mice. Modulating copper availability is a promising potential intervention to treat these diseases. However, the mechanisms underlying the beneficial impact of copper modulation in disease are poorly understood. Moreover, the role of copper homeostasis in immune function, including in T cell responses, is not clear. Copper is a required cofactor for proteins involved in essential T cell processes, including extracellular matrix regulation, signaling pathways, mitochondrial metabolism, autophagy, and maintenance of reactive oxygen species. To investigate the impact of copper levels on T cell function, we examined T cell activation during altered copper availability. We found that copper chelation limited T cell proliferation and reduced expression of activation markers following stimulation. We also found that both activation and copper availability altered copper transporter expression in T cells. Additionally, copper modulation substantially impacted the transcriptional profiles of activated T cells, including expression of transcription factors, co-stimulatory markers, cytokines, and metabolic genes. Overall, our data demonstrate that altered copper levels impair T cell activation. Further, our results reveal new pathways impacted by copper homeostasis in T cells, which will be key to both understanding the role of copper in disease and leveraging this role for therapeutic development. Studies to evaluate the role of copper homeostasis in the immune response in vivo are ongoing. Supported by funding from ALSAC.