<i>Mycobacterium tuberculosis</i> Impedes CD40-Dependent Notch Signaling to Restrict Th <sub>17</sub> Polarization During Infection

Abstract

Early Th17 responses are necessary to provide protection against Mycobacterium tuberculosis (Mtb). However, we previously demonstrated that Mtb restricts Th17 polarization and that engaging the CD40 costimulatory pathway on dendritic cells (DCs) enhances Th17 responses and augments Mtb control. Defining the molecular mechanisms that limit Th17 polarization during Mtb infection will facilitate the design of TB vaccination strategies that induce protective Th17 immunity. Here, we identify the Notch ligand, Delta-like ligand 4 (DLL4), as necessary for Th17 polarization and demonstrate that Mtb limits DLL4 signaling on DCs to prevent optimal Th17 responses. While Mtb infection induced only low levels of Dll4 mRNA in DCs, exogenously engaging CD40 on Mtb-infected DCs enhanced Dll4 expression and led to high frequencies of DLL4+ and DLL4+ Jagged1+ DCs. Antibody blockade of DLL4 on DCs reduced Th17 polarization but did not affect Th1 polarization. DLL4 was also required for inducing multifunctional CXCR3+ CCR6+ CD4 T cells co-expressing IL-17, IL-22 and IFN-γ in the lungs of mice, and DLL4-dependent Th17 responses inversely correlated with Mtb lung burdens. Additionally, 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 Notch ligand signaling to restrict Th17 responses and identify the CD40-DLL4 pathways as targets for developing new Th17-inducing vaccines and adjuvants for TB.