2018 Fiscal Year Annual Research Report
Role of NR4A2 in pathogenic Th cells in autoimmune diseases
| Project/Area Number |
17K16135
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| Research Institution | National Center of Neurology and Psychiatry |
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Principal Investigator |
Raveney Benjamin 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 免疫研究部, 科研費研究員 (70795385)
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Keywords | Autoimmunity / Multiple Sclerosis / T cells / Th17 |
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| Outline of Annual Research Achievements |
Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS) results from activation of self-reactive T helper (Th) cells against CNS antigens. Despite many years of study, the features of authentic pathogenic Th cells in this disease remain elusive.
Using a mouse model of MS, we revealed that Th cells require the gene NR4A2 to develop full pathogenic responses. Thus, we aimed to investigate the role of NR4A2 in genuine pathogenic Th cells activated against self-antigens in the CNS.
Using single-cell transcriptome analysis, we compared CNS-infiltrating Th cells under conditions where pathogenic responses were formed and under conditions where pathogenic responses were unable to be generated. We conducted new bioinformatic studies of published data sets, which guided our investigation of potential pathogenic Th cell-related genes. We found that a particular subset of Th cells, defined based on a unique expression profile, was eliminated in the absence of NR4A2 and pathogenic CNS-targeted responses. This cell subset greatly differs to previously reported "pathogenic" Th17 cells. Further, investigation indicates this new subset is pathogenic on transfer and perturbing key gene products associated with these cells reduces disease. Markers of our newly-defined pathogenic type Th cells have allowed investigation in human MS patients, and these studies indicate an increase in these Th cells during active periods of relapses in MS. It is hoped that future investigation of these T cells will lead to advances in diagnosis and treatments of active MS
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