SIRT2 inhibition by AGK2 enhances mycobacteria-specific stem cell memory responses by modulating beta-catenin and glycolysis

by Selleckchem | Jun 16 2023

Bacille Calmette-Guerin (BCG) generates limited long-lasting adaptive memory responses leading to short-lived protection against adult pulmonary tuberculosis (TB). Here, we show that host sirtuin 2 (SIRT2) inhibition by AGK2 significantly enhances the BCG vaccine efficacy during primary infection and TB recurrence through enhanced stem cell memory (TSCM) responses. SIRT2 inhibition modulated the proteome landscape of CD4+ T cells affecting pathways involved in cellular metabolism and T-cell differentiation. Precisely, AGK2 treatment enriched the IFNγ-producing TSCM cells by activating β-catenin and glycolysis. Furthermore, SIRT2 specifically targeted histone H3 and NF-κB p65 to induce proinflammatory responses. Finally, inhibition of the Wnt/β-catenin pathway abolished the protective effects of AGK2 treatment during BCG vaccination. Taken together, this study provides a direct link between BCG vaccination, epigenetics, and memory immune responses. We identify SIRT2 as a key regulator of memory T cells during BCG vaccination and project SIRT2 inhibitors as potential immunoprophylaxis against TB.

Comments:

The passage you provided highlights a study that explores the potential of enhancing the efficacy of the Bacille Calmette-Guerin (BCG) vaccine, which is used for tuberculosis (TB) prevention. The researchers focused on inhibiting a protein called sirtuin 2 (SIRT2) using a compound called AGK2. They found that SIRT2 inhibition significantly improved the effectiveness of the BCG vaccine by enhancing the generation of stem cell memory (TSCM) responses.

The study suggests that SIRT2 inhibition affects the proteome landscape (the set of proteins) in CD4+ T cells, which are a type of immune cells involved in coordinating the immune response. The altered proteome affected pathways related to cellular metabolism and T-cell differentiation.

Specifically, AGK2 treatment increased the population of TSCM cells that produce interferon gamma (IFNγ), an important cytokine involved in immune responses. This effect was attributed to the activation of β-catenin (a protein involved in the Wnt signaling pathway) and glycolysis (a metabolic process).

Additionally, SIRT2 was found to target specific proteins, such as histone H3 and NF-κB p65, leading to the induction of proinflammatory responses. This suggests that SIRT2 inhibition can promote an immune environment favorable for protective immune responses.

Importantly, the researchers demonstrated that the protective effects of AGK2 treatment during BCG vaccination were dependent on the Wnt/β-catenin pathway. When this pathway was inhibited, the enhanced vaccine efficacy provided by AGK2 was abolished.

In summary, this study provides insights into the role of SIRT2 in regulating memory T cells during BCG vaccination. It suggests that SIRT2 inhibitors, such as AGK2, have the potential to be used as immunoprophylaxis (preventive treatment) against TB, by enhancing the immune response and generating long-lasting memory immune cells.