Mycobacterium tuberculosis impedes CD40-dependent notch signaling to restrict Th₁₇ polarization during infection

Early Th₁₇ responses are necessary to provide protection against Mycobacterium tuberculosis (Mtb). Mtb impedes Th₁₇ polarization by restricting CD40 co-stimulatory pathway on dendritic cells (DCs). We previously demonstrated that engaging CD40 on DCs increased Th₁₇ responses. However, the molecular mechanisms that contributed to Th₁₇ polarization were unknown. Here, we identify the Notch ligand DLL4 as necessary for Th₁₇ polarization and demonstrate that Mtb limits DLL4 on DCs to prevent optimal Th₁₇ responses. Although Mtb infection induced only low levels of DLL4, engaging CD40 on DCs increased DLL4 expression. Antibody blockade of DLL4 on DCs reduced Th₁₇ polarization in vitro and in vivo. In addition, we show that the Mtb Hip1 protease attenuates DLL4 expression on lung DCs by impeding CD40 signaling. Overall, our results demonstrate that Mtb impedes CD40-dependent DLL4 expression to restrict Th₁₇ responses and identify the CD40-DLL4 pathways as targets for developing new Th₁₇-inducing vaccines and adjuvants for tuberculosis.