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

Author:

Yu Hong12,Nishio Hiroshi123,Barbi Joseph124,Mitchell-Flack Marisa12,Vignali Paolo D. A.125,Zheng Ying12,Lebid Andriana12,Chang Kwang-Yu16,Fu Juan12,Higgins Makenzie1,Huang Ching-Tai27,Zhang Xuehong8,Li Zhiguang8,Blosser Lee1,Tam Ada1,Drake Charles G.29ORCID,Pardoll Drew M.12

Affiliation:

1. Bloomberg-Kimmel Institute for Cancer Immunotherapy, Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine

2. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine

3. Department of Obstetrics and Gynecology, Keio University School of Medicine

4. Department of Immunology, Roswell Park Comprehensive Cancer Center

5. University of Pittsburgh

6. National Institute of Cancer Research, National Health Research Institutes

7. Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital

8. Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University

9. Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center

Abstract

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.

Publisher

eLife Sciences Publications, Ltd

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