In vivo analysis of factors affecting the dynamics of the adaptive immune response to M. tuberculosis and contributing to bacterial persistence
- Author(s): Wolf, Andrea J
- Advisor(s): Ernst, Joel D
- et al.
M. tuberculosis has persisted as one of the most prevalent and deadly human pathogens in large part because of its ability to evade the host immune system. In addition to several cellular based evasion mechanisms have been described, the adaptive immune response to M. tuberculosis exhibits significantly delayed timing compared to most pathogens. As a result M. tuberculosis is able to grow unchecked, expanding >20,000-fold in the first 3 weeks in the lungs. The immune response that does develop only controls, but does not eliminate the infection, resulting in a chronic infection posing a constant threat to the host. Utilizing green fluorescent protein (GFP)-expressing M. tuberculosis we quantitated and characterized the infected cell subsets in the lungs determining that dendritic cells account for the largest percentage of infected cells after 2 weeks of infection and they transport a portion of the bacteria to the draining lymph node in a CCL19/CCL21-dependent manner. Incorporating the adoptive transfer of M. tuberculosis-specific transgenic CD4+ T cells into the studies demonstrated that CD4+ T cell activation in the draining lymph node is delayed until a threshold number of bacteria reached the lymph node. Impaired dendritic cell migration to the draining lymph node resulted in fewer bacteria and consequently delayed the adaptive immune response even further. One of the rate-limiting steps in the adaptive immune response to M. tuberculosis is the transport of bacteria by dendritic cells to the draining lymph node. Considering the rapid maturation of infected dendritic cells, we hypothesize that M. tuberculosis initially infects a non-migrating cell compartment and a round of bacteria growth and spread is necessary in order to infect sufficient numbers of dendritic cells to achieve transport of the threshold number of bacteria needed to initiate a T cell response. Lastly, we show that after the first 3 weeks of infection there is a significant decrease in the ability to stimulate Antigen 85B-specific T cells potentially contributing to the ability of M. tuberculosis to establish a chronic infection.