Nucleus accumbens-associated protein 1 (NAC1) is a transcription co-factor that has been shown to possess multiple roles in stem cell and cancer biology. However, little is known about its roles in regulation of the immune system. In the current study, we observed that expression of NAC1 impacted the survival of CD8⁺ T cells in vitro. NAC1^−/− CD8⁺ T cells displayed lower metabolism, including reduced glycolysis and oxidative phosphorylation. In vivo, compared with wild-type (WT) mice, NAC1^−/− mice produced a lower response to vaccinia virus (VACV) infection, and viral antigen (Ag)-specific CD8⁺ T cells decreased more slowly. Additionally, we observed that the NAC1^−/− mice demonstrated a stronger memory formation of viral Ag-specific CD8⁺ T cells post-viral infection. Mechanically, we identified that compared with WT CD8⁺ T cells, the Interferon Regulatory Factor 4 (IRF4), a key transcription factor in T cell development, was highly expressed in NAC1^−/− CD8⁺ T cells, insinuating that IRF4 could be a critical regulatory target of NAC1 in the memory formation of CD8⁺ T cells. Our results indicate that NAC1 restrains the memory formation of CD8⁺ T cells by modulating IRF4, and targeting NAC1 may be exploited as a new approach to boosting CD8⁺ T cell memory.

The nucleus accumbens-associated protein 1 (NAC1) has recently emerged as a pivotal factor in oncogenesis by promoting glycolysis. Deletion of NAC1 in regulatory T cells (Tregs) has been shown to enhance FoxP3 stability, a suppressor of glycolysis. This study delves into the intriguing dual role of NAC1, uncovering that Treg-specific deletion of NAC1 fosters metabolic fitness in Tregs, thereby promoting tumorigenesis. Our results unveil that NAC1-deficient Tregs exhibited prolonged survival and heightened function, particularly in acidic environments. Mechanistically, we find that NAC1-deficient Tregs adapted to adverse conditions by upregulating FoxP3 expression, engaging in CD36-mediated lipid metabolism, and enhancing peroxisome proliferator–activated receptor gamma coactivator 1-alpha–regulated mitochondrial function. In mouse tumor xenograft models, NAC1-deficient mice demonstrated increased susceptibility to tumor growth. Notably, Tregs lacking NAC1 not only displayed elevated lipid metabolism and mitochondrial fitness but also exhibited enhanced tumoral infiltration. Adoptive Treg transfer experiments further underscored the supportive role of NAC1-deficient Tregs in tumor growth. These findings suggest that modulating NAC1 expression in FoxP3 ⁺ Tregs could serve as a promising approach to augment antitumor immunity. Understanding the intricate interplay between NAC1 and Tregs opens avenues for potential therapeutic strategies targeting the tumor microenvironment.

The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression.

The immune system functions as a sophisticated defense mechanism, shielding the body from harmful pathogenic invaders

In this study, we revealed a critical role of eukaryotic elongation factor-2 kinase (eEF-2K), a negative regulator of protein synthesis, in regulating T cells during vaccinia virus (VACV) infection. We found that eEF-2K-deficient (eEF-2K⁻/⁻) mice exhibited a significantly higher proportion of VACV-specific effector CD8⁺ T cells without compromising the development of VACV-specific memory CD8⁺ T cells. RNA sequencing demonstrated that eEF-2K⁻/⁻ VACV-specific effector CD8⁺ T cells had enhanced functionality, which improves their capacity to combat viral infection during the effector phase. Moreover, we identified tumor necrosis factor receptor-associated factor 3 (TRAF3) as a critical mediator of the stronger antiviral response observed in eEF-2K⁻/⁻ effector CD8⁺ T cells. These findings suggest that targeting eEF-2K may provide a novel strategy to augmenting effector CD8⁺ T cell responses against viral infections.