Memory T and B cells constitute our primary system of defense against reoccurring infectious disease, and therefore the ability to form these cells is the ultimate goal of vaccination. My laboratory is interested in understanding how memory T cells are generated during infection and vaccination, and why, in some circumstances, an immunization fails to induce long-term T cell immunity. Using several powerful model systems of infection in mice, we are beginning to elucidate the mechanisms involved in the development of protective and long-lived memory T cells. Our studies are aimed at identifying the signals and genetic pathways that regulate the differentiation of naïve CD8 T cells into effector cells and then into long-lived memory cells during the viral and bacterial infections of lymphocytic choriomeningitis virus and Listeria monocytogenes in mice.
Upon infection, naïve CD8 T cells encounter antigen and become activated. This triggers the cells to rapidly divide and undergo massive clonal expansion. This activation also induces the cells to differentiate into effector T cells that can secrete cytokines and kill infected cells, and this leads to rapid clearance of the pathogen within a week's time. Following the resolution of infection, the effector cell population begins to contract; the majority of the cells die by apoptosis over the next 2–3 weeks. However, a minority of cells (~5–10 percent) escape this period of cell death. The cells that survive become the long-lived memory cell population. The number of memory cells remains remarkably constant over time; this is due to their ability to self-renew by undergoing slow, periodic turnover, which we refer to as homeostatic turnover. These cells can protect against secondary infections.
We are interested in a central question in memory T cell development: What are the decisive factors that determine which of the effector cells will survive and become long-lived memory cells and which will die during the contraction phase? Recently, we identified that the cytokine interleukin-7 (IL-7) plays an important role in this decision and that a subset of effector cells express higher levels of the IL-7 receptor (IL-7R). The heightened level of IL-7R predisposes this subset of effector cells to survive and preferentially develop into long-lived memory T cells. Thus, the increased expression of IL-7R on effector CD8 T cells during infection helps to identify the memory cell precursors and provides an excellent tool with which to investigate the signals and mechanisms that regulate memory T cell development.
Recently we found that certain inflammatory cytokines, such as IL-12, promote the terminal differentiation of effector CD8 T cells (which express lower amounts of IL-7R). This is associated with increased levels of the transcription factor T-bet (encoded by Tbx-21). Our findings suggested that T-bet expression could act as a rheostat to modulate effector and memory T cell potential in CD8 T cells. We are examining the role of other key transcription factors in the development of memory CD8 T cells. Furthermore, we are extending these types of questions to CD4 T cells to determine if similar mechanisms underlie the formation of Th1 memory CD4 T cells. We are also initiating studies in mouse models of asthma to characterize the formation of allergen-specific Th2 CD4 T cells. Overall, our studies will help to improve the design of vaccines and immunotherapies aimed at fighting cancer, asthma and chronic infection.
Grants from the National Institutes of Health, the Burroughs Wellcome Fund, the Edward Mallinckrodt Jr. Foundation, the Cancer Research Institute, and the American Asthma Foundation provided support for these projects.
As of May 30, 2012