NAC1 Modulates Autoimmunity by Suppressing Regulatory T Cell- Mediated Tolerance

Yang, J.-M.; Ren, Y.; Kumar, A.; Xiong, X.; das, j.; Peng, H.-y.; Wang, L.; Ren, X.; Alainz, R. C.; de Figueiredo, P.; Fang, D.; Liu, X.; Wang, J.; Song, J. J.

doi:10.1101/2022.03.01.482525

bioRxiv · 10.1101/2022.03.01.482525

NAC1 Modulates Autoimmunity by Suppressing Regulatory T Cell- Mediated Tolerance

Yang, J.-M.·Ren, Y.·Kumar, A.·Xiong, X.·das, j.·Peng, H.-y.·Wang, L.·Ren, X.·Alainz, R. C.·de Figueiredo, P.·Fang, D.·Liu, X.·Wang, J.·Song, J. J.

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Abstract

FoxP3+ regulatory T cells (Tregs) are a distinct subset of CD4+ T cells integral to the maintenance of the balance of the immune system, and their dysregulation is a trigger of autoimmunity. 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 Tregs and a critical determinant of immune tolerance. Phenotypically, NAC1-/- mice show substantial tolerance to the induction of autoimmunity, as evidenced by the significantly decreased occurrences of autoimmune arthritis and colitis. Analysis of T cells from the wild-type (WT) or NAC1 knockout (-/-) mice found that NAC1 is crucially involved in the early stage of T cell development. NAC1 positively affects CD8+ T cell differentiation, but negatively regulates Treg development. Compared with WT animals, NAC1-/- mice displayed defects in CD8+ T cell development but generated a larger amount of CD4+ regulatory Tregs that exhibit a higher metabolic profile and immune suppressive activity, increased acetylation, and expression of FoxP3, and slower turnover of this transcriptional factor. Furthermore, treatment of Tregs with the pro-inflammatory cytokines IL-1{beta} or TNF- induced a robust upregulation of NAC1 but an evident downregulation of FoxP3 as well as the acetylated FoxP3, suggesting that the reduction of FoxP3 by the NAC1-mediated deacetylation and destabilization of this lineage-specific transcriptional factor contributes considerably to break of immune tolerance. These findings imply that the pro-inflammatory cytokines-stimulated upregulation of NAC1 acts as a trigger of the immune response through destabilization of Tregs and suppression of tolerance induction, and that therapeutic targeting of NAC1 warrants further exploration as a potential tolerogenic strategy for treatment of autoimmune disorders.

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Yang, J.-M., Ren, Y., Kumar, A., Xiong, X., das, j., Peng, H.-y., Wang, L., Ren, X., Alainz, R. C., de Figueiredo, P., Fang, D., Liu, X., Wang, J., Song, J. J.. 2022-03-04. NAC1 Modulates Autoimmunity by Suppressing Regulatory T Cell- Mediated Tolerance. https://doi.org/10.1101/2022.03.01.482525

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