PROTECTIVE CD8 T CELL RESPONSES to TUBERCULOSIS - Project Summary. Mycobacterium tuberculosis (Mtb) is a leading cause of human deaths around the world. Despite eliciting a vigorous immune response, Mtb evolved to adapt to its host and evade clearance. While this idea was originally based on its ability to survive in the phagosome and avoid antibody immunity, we now know that Mtb also avoids T cell immunity. Mtb elicits strong CD8 T cell responses in people and CD8 T cell responses contribute to protection against Mtb in animal models. My research program has discovered that (1) not all Mtb- specific T cells recognize Mtb-infected macrophages; (2) CD8 T cells require CD4 help to maintain effector function and avoid exhaustion; and (3) memory CD8 T cells are not always as fit as naïve CD8 T cells. These factors contribute to the difficulty in observing a role for CD8 T cells in murine TB. By better characterizing how CD8 T cells recognize infected macrophages and control Mtb infection, we expect to gain insight into the role that CD8 T cells serve in immunity to Mtb. My lab has developed an innovative and productive research program that seeks to understand how CD8 T cells restrict bacterial growth and how Mtb defeats CD8 immunity. Our goal is to find new ways to elicit protective CD8 T cell responses that can inform vaccine strategies to prevent or treat TB. In Aim 1, we will combine the use of a BCG prime/ChAd.TB boost vaccine strategy that induces protective CD8 T cell responses, t-bet fate reporter mice to track memory CD8 T cells, and a novel model of latent TB infection (LTBI). This approach will permit us to characterize how vaccine-elicited CD8 T cells are recalled following Mtb challenge, identify protective antigens recognized by CD8 T cells, discover correlates of protection, and determine the role of CD8 T cells during LTBI. The focus of Aim 2 is disentangle how the lack of CD4 help and high Mtb CFU lead to dysfunctional CD8 T cells. The molecular differences between helped and unhelped CD8 T cells will be used to determine the molecular basis of protection mediated by CD8 T cells. We previously showed that CD8 T cells specific for the immunodominant TB10.4 antigen poorly recognize Mtb-infected macrophages. However, other CD8 T cells recognize Mtb-infected macrophages and efficiently inhibit Mtb replication. We have developed an experimental pipeline to identify Mtb antigens presented by infected macrophages, which we hypothesize will be ideal vaccine targets which will be the focus of Aim 3. Finally, Aim 4 will leverage the differences between protective vs. nonprotective vaccine-elicited CD8 T cell responses (Aim 1), and helped vs. exhausted CD8 T cells (Aim 2), to identify the pathways that license effector CD8 T cell activity, and perform mechanistic studies that ascertain the pathways that inhibit intracellular Mtb growth. By expanding our understanding of how effector and memory CD8 T cells participate in immunity to TB, our research program will provide actionable concepts to incorporate into novel TB vaccine strategies.
