Decisions on the road to memory.

A fundamental property of the adaptive immune system is the ability to generate antigen-specific memory, which protects against repeated infections with the same pathogens and determines the success of vaccination. Immune memory is built up alongside a response providing direct protection during the course of a primary immune response. For CD8 T cells, this involves the generation of two distinct types of effector cells. Short lived effector cells (SLECs) confer immediate protection, but contribute little to the memory repertoire. Memory precursor effector cells (MPECs) have the ability to respond to survival signals and develop into memory cells. These two types of cells can be distinguished on the basis of surface markers and express distinct genetic programs. A single naive CD8 T cell can give rise to both MPEC and SLEC daughter cells. This may involve an initial asymmetric division or depend on later instructive signals acting on equipotent daughter cells. Strong inflammatory signals favor the generation of SLECs and weaker inflammation favors the generation of MPECs. A distinguishing feature of MPECs is their ability to persist when most effector cells die. This survival depends on signals from the IL-7 receptor, which induce expression of anti-apoptotic factors. MPECs are therefore characterized by expression of the IL-7 receptor as well as the CCR7 chemokine receptor, which allows homing to areas in lymphoid organs where IL-7 is produced. Critical for persistence of MPECs is further their responsiveness to myeloid cell derived IL-15, which instructs these cells to switch their metabolic programs from glycolysis associated with rapid proliferation to fatty acid oxidation required during a more resting state. As the mechanisms determining generation of immunological memory are unraveled, opportunities will emerge for the improvement of vaccination strategies.