Spermidine suppresses DC activation via eIF5A hypusination and metabolic adaptation.

Introduction: Cell metabolism plays an important role in immune effector responses and through responding to metabolic signals, immune cells can adapt and regulate their function. Arginine metabolism in dendritic cells (DC) has been shown to reduce T cell activation; however, it is unclear how this immunosuppressive state is induced. Method: To address this issue, we examined the immunomodulatory capacity of various metabolites from arginine metabolism. Results: Through the use of a recently described DC:T cell interaction assay and flow cytometry we demonstrated that spermidine most significantly inhibited DC activation, preventing subsequent interactions with CD4 T cells. DC function could be restored by addition of inhibitors of spermidine metabolism via the eIF5A-hypusine axis, required for expression of some mitochondrial enzymes. We also demonstrated that the spermidine induced-immunosuppressive state protected DC against activation-induced loss of mitochondrial capacity for energy generation, which was also hypusination dependent. Conclusion: Taken together, these data demonstrate that spermidine is the key immunomodulatory component downstream of arginine metabolism and that it mediates this effect by stimulating hypusination-dependent protection of OXPHOS in DC, which in turn results in a reduced ability of DC to activate and interact with T cells. This pathway may be utilized by the immune system to regulate excessive immune responses but could also be exploited by pathogens as a method of immune evasion.