2017 Fiscal Year Research-status 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 |
The autoimmune disease multiple sclerosis (MS) is associated with activation of self-reactive T helper (Th) cells. The character and mechanisms of pathogenic Th cells in this disease have been long-studied, but remain unclear. In EAE, a model of MS, pathogenic responses are reduced in mice lacking the gene NR4A2 in Th cells.
We aimed to investigate the role of NR4A2 in T cell activation against self-tissues and reveal mechanisms of pathogenic responses by self-reactive Th cells.
We compared CNS-infiltrating Th cells in EAE with and without NR4A2 using single cell expression analysis to identify genes associated with pathogenic Th cells.
NR4A2 may be associated with controlling intracellular signal strength following TcR engagement, thus licensing T cell activation of low avidity responses, this may be a key determinant in autoreactive responses. To examine this mechanistically, we compared TcR signaling in T cells with or without NR4A2 using conditional ko mice. We have discovered that there are phosphorylation kinetic differences in a number of adapter molecules in the absence of NR4A2, suggesting that additional pathways are activated by low level signals in an NR4A2 dependent manner. Such signals are redundant in T cells stimulated by a high avidity (foreign) response.
Experiments using the BXSB model of spontaneous autoimmune disease, where NR4A2 is required for T cell-mediated production of autoantibodies, but not anti-foreign antibodies by B cells have also indicated how NR4A2 up regulation in T cells can shape how self-reactive T cells make response to auto antigens.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We have determined a number of novel genes associated with pathogenic Th cells in a NR4A2-dependent manner by single cell transcriptome clustering analysis. These data have been compared with expression analysis of in vitro generated "pathogenic" Th17 cells and has enabled us to revise the authentic pathogenic gene set separately from previously studied gene sets that merely represent in vitro cell differentiation.
We have also determined signaling molecules downstream of TcR activation that are associated with NR4A2-dependent responses.
These findings are in line with our research plan and set the stage for future studies in this project as well as contributing to the advancement of scientific knowledge of this field.
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| Strategy for Future Research Activity |
I will continue these works according to the previous research plan. Experiments will focus on elucidating the mechanistic role of NR4A2 in tuning T cell activation of self-reactive T cells in autoimmune disease using mouse models as well as translational studies in human disease (MS) to determine how such mechanisms may be useful in providing therapeutic targets to treat human autoimmunity.
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| Causes of Carryover |
I have saved money where possible on purchase of consumables and travel expenses.
I plan to use it mainly for reagents and consumables for this project in the next fiscal year.
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[Presentation] Characterization of novel Eomes-positive cytotoxic T helper cells in chronic autoimmune CNS inflammation2017
Author(s)
Raveney, B.J.E., Lin, Y., Sato, W., Oki, S., Yamamura, T.
Organizer
British Society for Immunology Annual Congress, Brighton, UK
Int'l Joint Research
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