Abstract
Mycobacterium tuberculosis (Mtb) impairs dendritic cell (DC) functions and induces suboptimal antigen-specific CD4 T cell immune responses that are poorly protective. Mucosal T-helper cells producing IFN-γ (Th1) and IL-17 (Th17) are important for protecting against tuberculosis (TB), but the mechanisms by which DCs generate antigen-specific T-helper responses during Mtb infection are not well defined. We previously reported that Mtb impairs CD40 expression on DCs and restricts Th1 and Th17 responses. We now demonstrate that CD40-dependent costimulation is required to generate IL-17 responses to Mtb. 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 antigen-specific IL-17 responses. 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, we show that 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 CD40 costimulation by DCs plays an important role in generating antigen-specific Th17 cells and targeting the CD40-CD40L pathway represents a novel strategy to improve adaptive immunity to TB.
Highlights
Critical to the success of Mycobacterium tuberculosis (Mtb) as a pathogen is its ability to manipulate host innate and adaptive immune responses to its benefit
We previously reported that an avirulent hip1 (Hydrolase important for pathogenesis 1; Rv2224c) mutant Mtb strain induced significantly higher IL-17 and IFN-γ responses compared to infection with wild type Mtb due to enhanced functions of infected dendritic cell (DC) [20, 21]
We show that CD40 expression on DCs is required for the generation of IL-17 responses to Mtb infection and that interaction between CD40 on DCs and CD40L on CD4 T cells is critical for generating antigen-specific IL-17 responses
Summary
Critical to the success of Mycobacterium tuberculosis (Mtb) as a pathogen is its ability to manipulate host innate and adaptive immune responses to its benefit. We previously reported that an avirulent hip (Hydrolase important for pathogenesis 1; Rv2224c) mutant Mtb strain induced significantly higher IL-17 and IFN-γ responses compared to infection with wild type Mtb due to enhanced functions of infected DCs [20, 21]. Together, these studies suggest that wild type Mtb subverts DCs to prevent optimal T-helper responses and that augmenting DC functions during infection may be beneficial for improving protective immunity. To gain insight into host pathways involved in generating Th17 responses during Mtb infection, we sought to define the molecular mechanisms underlying Th17 responses following Mtb infection of DCs
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