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

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 en-hances the BCG vaccine efficacy during primary infection and TB recurrence through enhanced stem cell memory (TSCM) responses. SIRT2 inhibition modu-lated the proteome landscape of CD4+ T cells affecting pathways involved in cellular metabolism and T-cell differentiation. Precisely, AGK2 treatment en-riched the IFNg-producing TSCM cells by activating (3-catenin and glycolysis. Furthermore, SIRT2 specifically targeted histone H3 and NF-kB p65 to induce proinflammatory responses. Finally, inhibition of the Wnt/(3-catenin pathway abolished the protective effects of AGK2 treatment during BCG vaccination. Taken together, this study provides a direct link between BCG vaccination, epige-netics, 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.