Th17 immunity to tuberculosis requires CD40-CD40L interaction and is enhanced by CD40 engagement on Mycobacterium tuberculosis-infected dendritic cells

Abstract

Abstract Mycobacterium tuberculosis (Mtb) impairs dendritic (DC) cell functions and induces suboptimal antigen-specific CD4 T cell immune responses that are poorly protective. Mucosal T-helper 17 (Th17) cells have emerged as important for protecting against tuberculosis (TB), but the mechanisms involved in generating antigen-specific Th17 responses during Mtb infection are not well defined. We previously reported that Mtb restricts Th17 responses and impairs CD40 expression on dendritic cells (DCs). We now demonstrate that generating IL-17 responses to Mtb requires CD40-dependent costimulation. CD40-deficient DCs were unable to induce antigen-specific IL-17 responses after Mtb infection despite the production of Th17-polarizing innate cytokines. Disrupting the interaction between CD40 on DCs and its ligand CD40L on antigen-specific CD4 T cells, genetically or via antibody blockade, significantly reduced generation of antigen specific IL-17 responses; cytokines were unable to compensate for this reduction. Importantly, engaging CD40 on DCs with a multimeric CD40 agonist (CD40LT) enhanced antigen-specific IL-17 generation in ex vivo DC-T cell co-culture assays. Further, intratracheal instillation of Mtb-infected DCs treated with CD40LT significantly augmented antigen-specific Th17 responses in vivo in the lungs and lung-draining lymph nodes of mice. Finally, boosting CD40-CD40L interactions promoted balanced Th1/Th17 responses in a setting of mucosal DC transfer, and conferred enhanced control of lung bacterial burdens following aerosol challenge with Mtb. Our results demonstrate that targeting the CD40-CD40L pathway represents a novel strategy to enhance early Th17 responses and improves adaptive immunity to TB.