Tuberculosis (TB) has been a prevalent cause of morbidity and mortality in human beings for centuries, and is still a global health emergency today. Although not the headline of news in the United States, TB is rampant is sub-Saharan Africa and southeast Asia, where it is the number one killer of patients with acquired immunodeficiency syndrome (AIDS). Of the estimated 2 billion people infected with Mycobacterium tuberculosis (Mtb), the etiological agent responsible for TB, only a small percentage progress to active, contagious disease. This is because the immune system of most infected individuals is capable of effectively containing the infection, whereas in a percentage of individuals this containment will eventually fail, leading to reactivation of TB. Reactivation can arise due to numerous factors, including HIV infection, malnutrition, aging, or other immunosuppression. In some individuals, however, reactivation can occur without any overt immune deficiency. In this work, we sought to gain further understanding of the immunological mechanisms behind TB reactivation in susceptible individuals with otherwise intact immune systems.
The differences in susceptibility of human populations are also observed in mice. Inbred strains of mice generally fall into two main categories: those that are relatively resistant to TB reactivation, and those that are relatively susceptible. In this work, we used C57BL/6 mice as a representative of the resistant strains of mice, and CBA/J mice to represent susceptible strains. Previous work by our laboratory has identified a main correlate of reactivation susceptibility in CBA/J mice to be overproduction of the immunosuppressive cytokine, interleukin-10 (IL-10). CBA/J mice genetically deficient in IL-10, were resistant to Mtb reactivation and developed human-like TB lesions, a finding that is unprecedented in the field. We also more clearly defined the susceptibility of CBA/J mice to be the result of significant CD8+ T cell dysfunction. Additional studies demonstrated ways to enhance the immune response to Mtb by removing the inhibitory receptor, killer cell lectin-like receptor G1 (KLRG1), which we hypothesize could significantly shorten the treatment for TB. Overall, this collective work expands our understanding of how susceptibility to Mtb is mediated, and how protective responses may be enhanced to ease the burden of this devastating disease on humanity.