Engaging the CD40-CD40L pathway augments T-helper cell responses and improves control of Mycobacterium tuberculosis infection.

• Type of Material: Article
• Authors: Jonathan Kevin Sia, Emory University; Erica Bizzell, Emory University; Ranjna Madan-Lala, Emory University; Jyothi Rengarajan, Emory University
• Language: English
• Date: 2017-08-02
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2017 Sia et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1006530
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 13
• Issue: 8
• Start Page: e1006530
• End Page: e1006530
• Grant/Funding Information: This work was supported by grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health: 5R01AI083366-05 and 2R56AI083366-06A1 (to JR), a Yerkes National Primate Center base grant: RR000165 and a Center for AIDS research (CFAR) Immunology Core grant (to Emory University): P30AI050409.
• Research Categories: Health Sciences, Medicine and Surgery

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.