Mycobacterium tuberculosis (Mtb) is the leading cause of death worldwide from an infection. Mtb is able to evade innate immune defenses by growing in macrophages. Most people develop robust CD4+ T cell responses to Mtb infection, which is important for host defense; however, despite marked T cell responses, 5-10% of infected individuals will develop active tuberculosis (TB). The rationale behind this proposal is that if we better understood the basis of the partial protection conferred by CD4+ T cells, we could enhance those responses within the context of therapeutics to promote sterilizing immunity and such responses might serve as correlates of protection for vaccines. Since previous work showed that CD4+ T cells have to directly recognize antigen presenting cells in order to promote Mtb control, we sought to identify non-soluble factors that mediate macrophage-T cell interactions. We discovered that the cell surface receptor Signaling Lymphocyte Activating Molecule (SLAM) family member (SLAM/SLAMF1/CD150) is induced more than 400-fold in Mtb-infected macrophages in response to antigen specific CD4+ T cells. In addition, SLAMF1 was more highly expressed by infected macrophages as compared to uninfected macrophages in the same well. In addition, SLAMF1 was induced on T cells when they were incubated with infected macrophages. SLAMF1 signals through homotypic interactions; SLAMF1-expressing cells stimulate other SLAMF1-expressing cells. Thus, SLAMF1 is poised to mediate direct macrophage-T cell interactions and potentiate the antimicrobial activity of both cells. Previous studies established that SLAMF1 functions as a costimulatory molecule in CD4+ T cells, while in macrophages SLAMF1 activates the NADPH oxidase and lysosomal trafficking, antimicrobial responses that we previously showed are impaired during Mtb infection. Remarkably, we found that SLAMF1-induction in macrophages and T cells also correlates with protection in nonhuman primates vaccinated with IV BCG, which affords an unprecedented level of protection. Here, we will test our hypothesis that SLAMF1 signaling between infected macrophages and CD4+ T cells promotes control of Mtb, and that further enhancing SLAMF1 signaling boosts host protection. We will examine Slamf1 expression and localization to determine whether it is present on the cell surface, at the immunological synapse, in association with Mtb phagosomes, and regulated by Mtb infection and antigen specific T cells. We will determine its expression profile in nonhuman primate granulomas. We will establish whether SLAMF1 restricts intracellular growth of Mtb in human and murine macrophages and whether SLAMF1 activation enhances intracellular Mtb control. Finally, we will evaluate the importance of SLAMF1 in vivo. Thus, at the conclusion of this project, we will have established that SLAMF1 mediates macrophage- T cells signaling to promote intracellular control of Mtb. Our discoveries will enable future studies into the potential for targeting this pathway for therapeutic intervention and evaluating it as a correlate of protection. Given the immense global burden of TB, our project has the potential to make an enormous impact on human health.
Mycobacterium tuberculosis (Mtb) causes the disease tuberculosis (TB) and kills more people every year than any other infectious agent. The goal of this project is to better understand how macrophages and CD4+ T cells interact to confer protection to Mtb and whether these interactions can be enhanced to clear Mtb. These findings could lead to novel therapies and vaccines for TB.
