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

Bacille Calmette-Guerin (BCG) generates limited lengthy-lasting adaptive memory responses resulting in short-resided protection against adult lung t . b (TB). Here, we reveal that host sirtuin 2 (SIRT2) inhibition by AGK2 considerably improves the BCG vaccine effectiveness 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 with cellular metabolic process and T-cell differentiation. Precisely, AGK2 treatment enriched the IFN?-producing TSCM cells by activating ß-catenin and glycolysis. In addition, SIRT2 particularly targeted histone H3 and NF-?B p65 to induce proinflammatory responses. Finally, inhibition from the Wnt/ß-catenin path abolished the protective results of AGK2 treatment during BCG vaccination. Taken together, this research supplies a direct outcomes of BCG vaccination, epigenetics, and memory immune responses. We identify SIRT2 like a key regulator of memory T cells during BCG vaccination and project SIRT2 inhibitors as potential immunoprophylaxis against TB.