研究実績の概要 |
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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