Technological advances in recent years have allowed for an ever-expanding ability to analyze and quantify in vivo immune responses. MHC tetramers, intracellular cytokine staining, an increasing repertoire of transgenic and “knockout” mice, and the detailed characterization of a variety of infectious models have all facilitated more precise and definitive analyses of the generation and function of cytotoxic T lymphocytes (CTL). Understanding the mechanisms behind the differentiation of effector and memory CTL is of increasing importance to develop vaccination strategies against a variety of established and emerging infectious diseases. This review focuses on recent advances in our understanding of how effector and memory CTL differentiate and survive in vivo in response to viral or bacterial infection.

Immunization in the absence of CD4⁺ T cell help results in defective CD8⁺ T cell memory, deficient recall responses and diminished protective immunity. Here we investigated at what stage during the immune response to pathogen CD4⁺ T cells are essential in the promotion of functional CD8⁺ T cell memory. Memory CD8⁺ T cell numbers decreased gradually in the absence of CD4⁺ T cells despite the presence of similar numbers of memory cell precursors at the peak of the effector phase. Adoptive transfer of effector or memory CD8⁺ T cells into wild-type or CD4⁺ T cell–deficient mice demonstrated that the presence of CD4⁺ T cells was important only after, not during, the early CD8⁺ T cell programming phase. In the absence of CD4⁺ T cells, memory CD8⁺ T cells became functionally impaired and decreased in quantity over time. We conclude that in the context of an acute infection, CD4⁺ T cells are required only during the maintenance phase of long-lived memory CD8⁺ T cells.

Many strategies have been proposed to induce tolerance to transplanted tissue in rodents; however, few if any have shown equal efficacy when tested in nonhuman primate transplant models. We hypothesized that a critical distinction between specific pathogen-free mice and nonhuman primates or human patients is their acquired immune history. Here, we show that a heterologous immune response — specifically, virally induced alloreactive memory — is a potent barrier to tolerance induction. A critical threshold of memory T cells is needed to promote rejection, and CD8⁺ “central” memory T cells are primarily responsible. Finally, treatment with deoxyspergualin, an inhibitor of NF-κB translocation, together with costimulation blockade, synergistically impairs memory T cell activation and promotes antigen-specific tolerance of memory. These data offer a potential explanation for the difficulty encountered when inducing tolerance in nonhuman primates and human patients and provide insight into the signaling pathways essential for memory T cell activation and function.