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, certain immunizations fail 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 primarily aimed at identifying the signals 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 (LCMV) and Listeria monocytogenes in mice.

Upon infection, naïve CD8 T cells encounter antigen and become activated, and 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 and the majority of the cells die by apoptosis over the next 2-3 weeks. However, a minority of cells (~5-10%) escape this period of cell death and the cells that survive become the long-lived memory cell population. The number of memory cells remains remarkably constant over time and this is due to their ability to self-renewal by undergoing slow, periodic turnover that we refer to as ‘homeostatic turnover’, and these cells can protect against secondary infections.

A central question in memory T cell development is what is the decisive factor that determines 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 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 selective expression of IL-7R on effector CD8 T cells identifies the memory cell precursors, and this now provides an excellent tool in which to further investigate the signals and mechanisms that regulate memory T cell development. Overall, our studies will help to improve the design of vaccines and immunotherapies aimed at fighting cancer and chronic infection.

Kaech SM and Ahmed R. Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nat Immunol 5: 415-22 (2001).

Kaech SM, Wherry EJ and Ahmed R. Effector and memory T cell differentiation: implications for vaccine development. Nature Rev Immunol 4: 251-262 (2002).

Kaech SM, Hemby S, Kersh E and Ahmed R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell, 111: 837-851 (2002).

Hathcock K, Kaech SM, Ahmed R, Hodes R. Induction of telomerase activity and maintenance of telomere length in effector and memory T cells. J Immunol, 170: 147-152 (2003).

Kersh EN, Kaech SM, Onami T, Moran M, Wherry EJ, Miceli MC and Ahmed R. TCR Signal Transduction in Antigen-Specific Memory CD8 T Cells. J Immuno 170: 5455-63 (2003) .

Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, Ahmed R. Selective expression of the IL-7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol 4: 1191-98 (2003).

Chandele A and Kaech SM. Memory CD8 T cell maturation occurs independently of CD8aa.J Immunolin press (2005).