NAC1 confines virus-specific memory formation of CD4+ T cells through the ROCK1-mediated pathway

Abstract

Nucleus accumbens-associated protein 1 (NAC1), a transcriptional cofactor, has been found to play important roles in regulating regulatory T cells, CD8⁺ T cells, and antitumor immunity, but little is known about its effects on T-cell memory. In this study, we found that NAC1 expression restricts memory formation of CD4⁺ T cells during viral infection. Analysis of CD4⁺ T cells from wild-type (WT) and NAC1-deficient (^-/- ) mice showed that NAC1 is essential for T-cell metabolism, including glycolysis and oxidative phosphorylation, and supports CD4⁺ T-cell survival in vitro. We further demonstrated that a deficiency of NAC1 downregulates glycolysis and correlates with the AMPK-mTOR pathway and causes autophagy defective in CD4⁺ T cells. Loss of NAC1 reduced the expression of ROCK1 and the phosphorylation and stabilization of BECLIN1. However, a forced expression of ROCK1 in NAC1^-/- CD4⁺ T cells restored autophagy and the activity of the AMPK-mTOR pathway. In animal experiments, adoptively transferred NAC1^-/- CD4⁺ T cells or NAC1^-/- mice challenged with VACV showed enhanced formation of VACV-specific CD4⁺ memory T cells compared to adoptively transferred WT CD4⁺ T cells or WT mice. This memory T-cell formation enhancement was abrogated by forcing expression of ROCK1. Our study reveals a novel role for NAC1 as a suppressor of CD4⁺ T-cell memory formation and suggests that targeting NAC1 could be a new approach to promoting memory CD4⁺ T-cell development, which is critical for an effective immune response against pathogens.

Keywords: CD4+ T cells; NAC1; ROCK1; cellular metabolism; memory formation.