Suppression of the Immune Response Against Tuberculosis by Natural T Regulatory Cells

The causative agents of Tuberculosis (Tb), Mycobacterium tuberculosis and Mycobacterium bovis, subvert a number of host immune mechanisms to promote persistence of infection in the human host. Infection with these immunoevasive pathogens is estimated to cause 1.8 million deaths per year. The only Tb vaccine currently available is an attenuated form of M. bovis, called bacille Calmette Guerin (BCG), and its efficacy is highly variable. Thus, development of more effective vaccine strategies for Tb is of significant importance. Host-derived natural CD4+CD25+ T regulatory cells (Tregs) suppress host immune responses and prevent autoimmunity. However, Tregs can also interfere with protective immune responses against chronic infections or with the protective efficacy of vaccines. There is speculation that mycobacteria exploit the suppressive activity of Tregs to permit persistence in the host and that Treg activity also diminishes the protective efficacy of the BCG vaccine. Therefore, to explore the role of Tregs in anti-mycobacterial immunity, I first optimised a protocol to inactivate Tregs in vivo in a murine model, through administration of anti-CD25 monoclonal antibody. In addition, I developed a novel plasmid DNA replicon vaccine against Tb to aid with the assessment of the effect of Tregs on Tb vaccines. I hypothesised that inactivating Tregs in vivo prior to mycobacterial infection would enhance acute immune responses that are thought to be protective under current dogma and thereby enhance bacterial clearance. Enhanced immune responses were observed but, contrary to the hypothesis, inactivation of Tregs did not alter bacterial numbers in the lung. I also hypothesised that inactivating Tregs in vivo prior to live BCG or DNA vaccination would enhance primary and secondary immune responses that are thought to be protective against Tb infection and thereby enhance the protective efficacies of the vaccines. Enhanced vaccine-induced immune responses and accelerated secondary immune responses were observed for the BCG vaccine. However, Treg inactivation did not alter the protective efficacy of the BCG vaccine, and preliminary data suggests Treg inactivation may in fact decrease the protective efficacy of one plasmid DNA vaccine tested. In summary, this thesis illustrates that inactivating natural Tregs does not enhance protection from mycobacterial infection. This implies that inactivation of natural Tregs cannot be used in a therapeutic setting to enhance treatment or vaccination approaches for Tb. More importantly, Treg inactivation enhances immune responses that current dogma regard as protective against Tb infection, but does not correspondingly enhance protection. As a result of this disparity, this thesis questions the validity of measures that are commonly used as immune correlates of protection for Tb vaccine design. Ultimately, the development of more accurate immune correlates of protection for Tb will permit targeted design of more effective Tb vaccination strategies.