NAC1 modulates autoimmunity by suppressing regulatory T cell-mediated tolerance.
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We report here that nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the Broad-complex, Tramtrack, Bric-a-brac/poxvirus and zinc finger (BTB/POZ) gene family, is a negative regulator of FoxP3 in regulatory T cells (Tregs) and a critical determinant of immune tolerance. Phenotypically, NAC1-/- mice showed substantial tolerance to the induction of autoimmunity and generated a larger amount of CD4+ Tregs that exhibit a higher metabolic profile and immune-suppressive activity, increased acetylation and expression of FoxP3, and slower turnover of this transcription factor. Treatment of Tregs with the proinflammatory cytokines interleukin-1 or tumor necrosis factor- induced a robust up-regulation of NAC1 but evident down-regulation of FoxP3 as well as the acetylated FoxP3. These findings imply that NAC1 acts as a trigger of the immune response through destabilization of Tregs and suppression of tolerance induction, and targeting of NAC1 warrants further exploration as a potential tolerogenic strategy for treatment of autoimmune disorders.
author list (cited authors)
Yang, J., Ren, Y., Kumar, A., Xiong, X., Das, J. K., Peng, H., ... Song, J.
complete list of authors
Yang, Jin-Ming||Ren, Yijie||Kumar, Anil||Xiong, Xiaofang||Das, Jugal Kishore||Peng, Hao-Yun||Wang, Liqing||Ren, Xingcong||Zhang, Yi||Ji, Cheng||Cheng, Yan||Zhang, Li||Alaniz, Robert C||de Figueiredo, Paul||Fang, Deyu||Zhou, Hongwei||Liu, Xiaoqi||Wang, Jianlong||Song, Jianxun