Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity

The adaptive T cell response is accompanied by continuous rewiring of the T cell’s electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response. ### Competing Interest Statement CD is a co-inventor on patents licensed from JHU to BMS and Janssen and is currently an employee of Janssen Research. DMP is a consultant for Compugen, Shattuck Labs, WindMIL, Tempest, Immunai, Bristol-Myers Squibb, Amgen, Janssen, Astellas, Rockspring Capital, Immunomic, and Dracen, owns founders equity in ManaT Bio Inc., WindMIL, Trex, Jounce, Enara, Tizona, Tieza, and RAPT; and receives research funding from Compugen, Bristol-Myers Squibb, and Enara. None of the other authors have conflicting financial interests.