<i>Mycobacterium tuberculosis</i> modulates DC-T cell cross-talk and Th17 polarization by dampening Notch signaling

Abstract Tuberculosis (TB) is among the leading causes of death worldwide. While IFN-γ and CD4+ Th1 T cell responses are necessary to mount an immune response to Mycobacterium tuberculosis (Mtb), the causative agent of TB, they are not sufficient to provide protection. Studies from several groups, including our own, have highlighted an important role for IL-17 and Th17 responses in immunity to Mtb infection. Previous research from the laboratory has shown that Mtb restricts Th17 responses by dampening dendritic cell (DC) responses and has identified CD40-mediated co-stimulation as critical for generating Th17 responses in response to Mtb. We showed that exogenous CD40 engagement on Mtb-infected DCs enhances Th17 polarization and reduces Mtb burden in the lungs in a vaccination model. However, the DC mechanisms that mediate CD40-dependent Th17 polarization and protection have not been defined. Here we show that Notch signaling in DCs modulates DC-T cell crosstalk and influences T cell polarization during infection. Engaging the CD40 pathway on Mtb-infected DCs increases the mRNA and protein expression of Notch ligands DLL4 and Jagged1 over the course of infection. Blockade of Jagged1 during a DC-T cell co-culture lowers Th1 responses while blockade of both DLL4 and Jagged1 significantly limits Th17 polarization. These results reveal that during infection, Mtb restricts expression of Notch ligands, which impedes Th17 responses during TB. Insights from this study could be applied to designing more efficacious TB vaccines and adjuvants.