Lineage-Specific Metabolic Properties and Vulnerabilities of T Cells in the Demyelinating Central Nervous System
| Autor: | Scott M. Seki, Timothy N. J. Bullock, Max Stevenson, Abagail M. Rosen, Alban Gaultier, Lelisa Gemta, Sanja Arandjelovic |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
CD4-Positive T-Lymphocytes
Central Nervous System 0301 basic medicine Encephalomyelitis Autoimmune Experimental Multiple Sclerosis Encephalomyelitis Immunology Inflammation CD8-Positive T-Lymphocytes Biology Article Interferon-gamma Mice 03 medical and health sciences Myelin Immune system medicine Animals Immunology and Allergy Pyruvates Multiple sclerosis Interleukin-17 Experimental autoimmune encephalomyelitis Th1 Cells medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Th17 Cells Female Interleukin 17 medicine.symptom Glycolysis CD8 |
| Zdroj: | The Journal of Immunology. 198:4607-4617 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1600825 |
| Popis: | Multiple sclerosis (MS) is a disease that is characterized by immune-mediated destruction of CNS myelin. Current MS therapies aim to block peripheral immune cells from entering the CNS. Although these treatments limit new inflammatory activity in the CNS, no treatment effectively prevents long-term disease progression and disability accumulation in MS patients. One explanation for this paradox is that current therapies are ineffective at targeting immune responses already present in the CNS. To this end, we sought to understand the metabolic properties of T cells that mediate ongoing inflammation in the demyelinating CNS. Using experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, a well-studied model of MS, we showed that the CD4+ and CD8+ T cells that invade the EAE CNS are highly glycolytic. Elevated glycolytic rates in T cells isolated from the EAE CNS correlate with upregulated expression of glycolytic machinery and is essential for inflammatory responses to myelin. Surprisingly, we found that an inhibitor of GAPDH, 3-bromopyruvic acid (3-BrPa), blocks IFN-γ, but not IL-17A, production in immune cells isolated from the EAE CNS. Indeed, in vitro studies confirmed that the production of IFN-γ by differentiated Th1 cells is more sensitive to 3-BrPa than is the production of IL-17A by Th17 cells. Finally, in transfer models of EAE, 3-BrPa robustly attenuates the encephalitogenic potential of EAE-driving immune cells. To our knowledge, these data are among the first to demonstrate the metabolic properties of T cells in the demyelinating CNS in vivo. |
| Databáze: | OpenAIRE |
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