The Mycobacterium tuberculosis ESAT-6 protein inhibits differentiation of human monocytes to dendritic cells

Mycobacterium tuberculosis (Mtb) employs multiple strategies to evade host immunity, including disruption of antigen presentation. Dendritic cells (DCs) are crucial for effective antigen presentation and T-cell activation. In this study, we show that the mycobacterial protein ESAT-6 impairs monocyte to DC differentiation, with reduced expression of the DC markers CD209 and CD1a. ESAT-6 treatment elevated IL-6 and IL-10 levels, but blocking the biological activity of these cytokines failed to restore DC differentiation. Mechanistically, ESAT-6 suppressed phosphorylation of p65, establishing that ESAT-6 impairs DC differentiation by inhibiting NF-κB activation, a function dependent on the last six amino acids of its C-terminal domain. This mechanism may represent a novel immune evasion strategy employed by Mtb to subvert host adaptive immune responses during infection.