ESAT-6 protein of <i>Mycobacterium tuberculosis</i> inhibits differentiation of human monocytes to dendritic cells

Abstract 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 mycobacterial protein, ESAT-6, impairs monocyte to DC differentiation with reduced expression of the DC marker, CD209. ESAT-6 treatment elevated IL-6 and IL-10 levels, but blocking 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 and this function is 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.