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Metabolic regulation and function of T helper cells in neuroinflammation

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Abstract

Neuroinflammatory conditions such as multiple sclerosis (MS) are initiated by pathogenic immune cells invading the central nervous system (CNS). Autoreactive CD4+ T helper cells are critical players that orchestrate the immune response both in MS and in other neuroinflammatory autoimmune diseases including animal models that have been developed for MS. T helper cells are classically categorized into different subsets, but heterogeneity exists within these subsets. Untangling the more complex regulation of these subsets will clarify their functional roles in neuroinflammation. Here, we will discuss how differentiation, immune checkpoint pathways, transcriptional regulation and metabolic factors determine the function of CD4+ T cell subsets in CNS autoimmunity. T cells rely on metabolic reprogramming for their activation and proliferation to meet bioenergetic demands. This includes changes in glycolysis, glutamine metabolism and polyamine metabolism. Importantly, these pathways were recently also implicated in the fine tuning of T cell fate decisions during neuroinflammation. A particular focus of this review will be on the Th17/Treg balance and intra-subset functional states that can either promote or dampen autoimmune responses in the CNS and thus affect disease outcome. An increased understanding of factors that could tip CD4+ T cell subsets and populations towards an anti-inflammatory phenotype will be critical to better understand neuroinflammatory diseases and pave the way for novel treatment paradigms.

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Acknowledgements

We would like to thank Mary Collins for critical reading of and feedback for this manuscript. Because of the scope of this review, we apologize to investigators whose work and important contributions we could not highlight here. Some elements of the figures were adjusted from Servier Medical Art (http://smart.servier.com) as licensed under a Creative Commons Attribution License.

Funding

This work was supported by National Institutes of Health grants R01NS045937, R01NS30843, R01AI144166, P01AI073748, P01AI039671 and P01AI056299 (to VKK) and the Swiss National Science Foundation Postdoc Mobility Fellowship (to MS).

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  1. Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, USA

    Martina Spiljar & Vijay K. Kuchroo

  2. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA

    Martina Spiljar & Vijay K. Kuchroo

  3. Klareman Cell Observatory, Broad Institute, Cambridge, MA, USA

    Vijay K. Kuchroo

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Correspondence to Vijay K. Kuchroo.

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V.K.K. is cofounder of Celsius Therapeutics, Tizona Therapeutics, Larkspur Biosciences and Bicara Therapeutics. His interests are reviewed and managed by the Brigham and Women’s Hospital and Partners Healthcare in accordance with their conflict of interest policies.

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Spiljar, M., Kuchroo, V.K. Metabolic regulation and function of T helper cells in neuroinflammation. Semin Immunopathol 44, 581–598 (2022). https://doi.org/10.1007/s00281-022-00959-z

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