Friday, May 9, 2025
5/9/2025
The role of antigen-independent T cell activation in controlling M. tuberculosis infection - SUMMARY Tuberculosis (TB) is caused by the bacteria Mycobacterium tuberculosis (M.tb) and was responsible for 1.6 million deaths in 2021. The only licensed TB vaccine, the Bacillus Calmette-Guérin (BCG) vaccine, protects infants and children from disseminated disease but provides only partial protection in adult pulmonary disease. T cells are known to be critical in the host response to M.tb infection, but the mechanisms of this protection are not fully understood and further research is needed to develop new, effective vaccines. The first category of T cells are classical T cells that recognize peptide antigens presented by major histocompatibility (MHC) molecules and include two subsets, helper T cells that express the CD4 coreceptor (CD4 T cells) and cytotoxic T cells that express a CD8 coreceptor (CD8 T cells). The second category are nonclassical T cells that recognize non- peptide antigens via MHC independent mechanisms and consist of several distinct subsets. Two subsets of nonclassical T cells are CD1a/b/c restricted T cells and T cells that express a CD8 coreceptor (CD8 T cells). CD1a/b/c T cells recognize mycobacterial lipids presented by CD1a, CD1b, and CD1c molecules and have exhibited antimicrobial effector functions in response to M.tb infection. In contrast, the role of CD8 T cells in M.tb immunity is unknown. Antigen independent activation of T cells, termed bystander activation, occurs via proinflammatory cytokines and has been observed to have a protective effect in cancer and infection. Specifically in M.tb infection, bystander activation of noncognate memory T cells has shown a host protective impact by decreasing bacterial burden. CD8 T cells have exhibited higher levels of bystander activation compared to their CD8 classical counterparts. In contrast, the ability of CD1a/b/c restricted T cells to undergo bystander activation is unknown. Thus, CD1a/b/c restricted T cells are implicated in M.tb immunity, but their susceptibility to bystander activation has not been explored. Conversely, CD8 T cells are known to undergo bystander activation but their role in M.tb infection has not been established. In Aim 1, we will determine the ability of CD1a/b/c restricted T cells to undergo bystander activation, explore the underlying signaling mechanisms of this activation, and evaluate the ability of bystander activation to induce anti-bacterial effector programs during M.tb infection. In Aim 2, we will define the role of bystander activated CD8 T cells in M.tb infection, defining the antigen-independent functions of the subset on granuloma formation and bacterial control. Our proposal aims to fill the corresponding gaps in knowledge of the role of bystander activated CD1a/b/c restricted T cells and CD8 T cells during M.tb infection. In addition to potentially illuminating a novel pathway to target for M.tb vaccines, these studies will more comprehensively analyze T cell activation in M.tb immunity.
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