Two major problems contribute to the high global burden of TB: the ease of transmission of M. tuberculosis through the air, and the ability of M. tuberculosis to avoid elimination by adaptive immune responses. Therefore, the mechanisms that prevent T cells from eliminating M. tuberculosis are major roadblocks to developing efficacious TB vaccines. Since M. tuberculosis inhabits the antigen-presenting cells that are the targets for T cell recognition, the mechanisms that limit the efficacy of T cell responses in TB likely act at the level of antigen-presenting cells. For decades, it was believed that M. tuberculosis solely inhabits macrophages, but we and others have found that M. tuberculosis also resides in lung dendritic cells (DC) in mice and in humans. These findings may have a large impact on understanding TB immunity, as recent work in basic immunology has identified multiple subsets of DC with distinct properties, and our preliminary studies reveal that M. tuberculosis is found in the lungs of infected mice in alveolar macrophages (AM), neutrophils, recruited macrophages (RM), and 3 subsets of DC. Our preliminary studies also reveal that AM, RM, and DC differ markedly in their ability to activate M. tuberculosis antigen-specific CD4 T cells, suggesting that certain cell subsets contribute to protective immunity by activating CD4 effector T cells, while other subsets activate CD4 effector cells poorly and thus may be long-term reservoirs of the bacteria. We also discovered that M. tuberculosis-infected macrophages and DC release bacterial protein antigens in vivo and in vitro, and that the released antigens are processed and presented by uninfected cells to activate CD4 T cells. The overall hypothesis that drives the experiments in this application is that distinct subsets of mononuclear cells have different roles in TB pathogenesis and immunity, and that manipulating the populations or properties of mononuclear cells can improve the efficacy of T cell responses in TB.
In Aim 1, we will characterize the origins of the cells that harbor M. tuberculosis in the lungs, by characterizing their mechanisms of recruitment. We will also determine the mechanisms used by M. tuberculosis to spread from AM to RM and DCs in the lungs.
In Aim 2, we will extend our findings that AM, RM, and DC differ in their ability to activate CD4 effector T cells, to determine the mechanisms that mediate those differences and to guide therapeutic interventions to improve CD4 effector cell activation and immunological control of TB. We will also determine the importance of CD4 effector T cell activation by uninfected cells that have acquired antigens released by infected cells. Our results will guide efforts to improve the efficacy of antigen-specific T cell responses in TB: if antigen transfer from infected to uninfected cells is an immune evasion strategy, then strategies to prevent antigen transfer should be prioritized;in contrast, i antigen transfer and activation of T cells by uninfected cells contributes to control of M. tuberculosis, then efforts can be directed at optimizing the beneficial impact of this novel mechanism of T cell stimulation.
One of the major reasons that tuberculosis remains an enormous global health problem is that it has evolved to avoid elimination by our immune responses. This accounts for the ability of TB bacteria to persist in people and in populations of people, and accounts for the poor success of the current TB vaccine. Our work provides new approaches and new insights into how TB bacteria avoid elimination by immune responses, and will provide information that will guide development of successful TB vaccines.
|Srivastava, Smita; Ernst, Joel D (2014) Cell-to-cell transfer of M. tuberculosis antigens optimizes CD4 T cell priming. Cell Host Microbe 15:741-52|
|Srivastava, Smita; Ernst, Joel D; Desvignes, Ludovic (2014) Beyond macrophages: the diversity of mononuclear cells in tuberculosis. Immunol Rev 262:179-92|
|Srivastava, Smita; Ernst, Joel D (2013) Cutting edge: Direct recognition of infected cells by CD4 T cells is required for control of intracellular Mycobacterium tuberculosis in vivo. J Immunol 191:1016-20|
|Desvignes, Ludovic P; Ernst, Joel D (2013) Taking sides: interferons in leprosy. Cell Host Microbe 13:377-8|
|Bold, Tyler D; Davis, Daphne C; Penberthy, Kristen K et al. (2012) Impaired fitness of Mycobacterium africanum despite secretion of ESAT-6. J Infect Dis 205:984-90|
|Philips, Jennifer A; Ernst, Joel D (2012) Tuberculosis pathogenesis and immunity. Annu Rev Pathol 7:353-84|
|Blomgran, Robert; Desvignes, Ludovic; Briken, Volker et al. (2012) Mycobacterium tuberculosis inhibits neutrophil apoptosis, leading to delayed activation of naive CD4 T cells. Cell Host Microbe 11:81-90|
|Blomgran, Robert; Ernst, Joel D (2011) Lung neutrophils facilitate activation of naive antigen-specific CD4+ T cells during Mycobacterium tuberculosis infection. J Immunol 186:7110-9|
|Kwan, Candice K; Ernst, Joel D (2011) HIV and tuberculosis: a deadly human syndemic. Clin Microbiol Rev 24:351-76|
|Urdahl, K B; Shafiani, S; Ernst, J D (2011) Initiation and regulation of T-cell responses in tuberculosis. Mucosal Immunol 4:288-93|
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