Enhancing Pathogen-Specific Memory CD8+ T cell Responses In Vivo

Abstract Memory CD8+ T cells are essential adaptive effector cells of immune defenses because they are extremely efficient at sensing intracellular pathogens and tumors. The chief effector feature of CD8+ T cells is their ability to recognize and kill infected and “abnormal” cells but they also produce multiple effector cytokines and chemokines that contribute to orchestrate protective immune responses. The cellular and molecular mechanisms by which memory CD8+ T cells in vaccinated hosts are reactivated and mediate protection in vivo are not well understood. Answering this question has the potential to lead to novel strategies to harness or redirect the power of CD8+ T cells to the benefit of the host in many therapeutic contexts. Over the years, using mice immunized with the intracellular bacterium Listeria monocytogenes (Lm) as model, we have contributed to show that during recall infection, vaccine-induced memory CD8+ T cells quickly sense sets of inflammatory cytokines released from various antigen-presenting cells (APCs), which initiate a rapid effector program in the memory CD8+ T cells. This includes notably the secretion of the potent immunomodulatory cytokine IFNγ which further signals and activates microbicidal functions inside phagocytes, a necessary process for efficient protection of vaccinated hosts. More recently, during this funding period, we further established that, in addition to IFNγ, a set of three chemokines, CCL3, CCL4 and XCL1, produced concomitantly by the memory cells in response to cognate antigen (Ag) stimulation, are also required to achieve vaccinated host protection. We further demonstrated that these processes are spatially and temporally regulated, and that memory CD8+ T cells arrest in innate clusters of monocytes, and act as “catalysts” of their microbicidal effector functions. The next step of this work proposes to understand i) the genetic and epigenetic circuitry of cognate Ag-driven reactivation of the memory CD8+ T cell in vivo, ii) the chemotactic mechanisms coordinating the early Ly6C+ monocytic response and iii) the roles of the IFN-induced guanylate binding protein 1 (GBP1) in monocytes effector response. We use state of the art single cell approaches, intravital imaging, lentiviral engineering and new reporter/conditional mouse models to investigate these questions. We anticipate that successful completion of the proposed work will have a broad impact in the field of T cell biology, and vaccines, and potentially important therapeutic implications.