Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), is a successful pathogen that can strategically manipulate crosstalk between innate and adaptive immunity. Dendritic cells (DCs) are professional antigen-presenting cells that link innate immune recognition of M. tuberculosis to the development of antigen-specific CD4 T cells that combat infection. However, CD4 T cell immunity to infection is ultimately suboptimal. We investigate the role of DCs in the generation of CD4 T cell responses and methods to improve host immunity to infection and vaccination.
There is substantial evidence that IL-17 producing CD4 T cells (Th17) play an important role in protective immunity against M. tuberculosis. However, molecular mechanisms involved in the development of Th17 cells during infection are not fully defined. We show that DC co-stimulation through the CD40 pathway is required for the generation of antigen-specific Th17 cells. Further, we demonstrate that ligating CD40 on M. tuberculosis infected DCs augments Th17 polarization. Importantly, mucosal transfer of antigen-loaded, CD40-ligated DCs improves lung antigen-specific CD4 T cell responses and host control of M. tuberculosis infection. These results uncover a novel role for DC co-stimulation through CD40 in the development of Th17 cells during infection and provide evidence that engaging the CD40 pathway on DCs enhances immunity against M. tuberculosis.
We extend our studies to Bacillus Calmette-Guérin (BCG), an attenuated Mycobacterium bovis utilized as a TB vaccine with limited efficacy. We hypothesized that retention of immune subversion strategies by BCG limits its vaccine potential by hampering DC functions. Hip1 is an immune evasion protease in M. tuberculosis but its role in BCG was unknown. We demonstrate that DCs infected with BCG lacking hip1 (BCGΔhip1) are more mature, secrete increased levels of cytokines, and enhance CD4 T cells responses when compared to BCG. Notably, mucosal transfer of BCGΔhip1 infected DCs augments host control of lung bacterial burden following aerosol challenge with M. tuberculosis.
Our findings reveal that mycobacterial subversion of DCs attenuates the development of antigen-specific CD4 T cell immunity. We contribute insights into the role of DC co-stimulation during infection and improve host immunity in the context of infection and vaccination through DC-targeted strategies.
Table of Contents
TABLE OF CONTENTS:
Mycobacterium tuberculosis impairs dendritic cell functions through the serine hydrolase Hip1
Engaging the CD40-CD40L pathway augments T-helper cell responses and improves control of Mycobacterium tuberculosis infection
Deletion of BCG Hip1 protease enhances dendritic cell and CD4 T cell responses
Discussion and future directions
Innate Immune Defenses in Human Tuberculosis: An Overview of the Interactions between Mycobacterium tuberculosis and Innate Immune Cells
About this Dissertation
|Subfield / Discipline|
|Committee Chair / Thesis Advisor|
|Modulation of innate-adaptive immune crosstalk during Mycobacterium tuberculosis infection ()||2018-04-06||