Effector and memory T-cell differentiation: implications for vaccine development

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Abstract
Long-term T-cell memory can be attributed to the following characteristics of memory T-cell populations compared with naive T-cell populations: an increased frequency of antigen-specific precursors (∼1000-fold); changes in gene-expression profile that allow faster responses; re-distribution near the site of microbial entry; and homeostatic proliferation leading to longevity. Compared with CD4+ T cells, CD8+ T cells seem to be less dependent on co-stimulation for their initial activation. Two models have been proposed to explain this: either CD8+ T cells have lower activation thresholds or CD8+ T cells accumulate activation signals faster than CD4+ T cells. Both CD4+ and CD8+ T cells readily commit to a proliferative programme after a relatively brief period of stimulation with antigen. CD8+ T cells divide faster and show a greater level of clonal expansion than CD4+ T cells. For CD8+ T cells, commitment to proliferation is tightly coupled with commitment to effector- and memory-cell differentiation. This developmental programme might ensure that a large enough pool of memory T cells is formed despite decreasing levels of antigen at later stages of the response. Variations in the duration of signals (T-cell receptor or cytokines) might lead to the development of effector T-cell subsets with distinct effector and migratory patterns. The lineage of memory T cells is not fully understood, but available evidence suggests that memory cells can be derived from effector cells or alternatively, in some cases without passing through an effector stage. The extent of cell death determines the size of the memory T-cell pool; this might be regulated by interleukin-2 family cytokines, molecules of the tumour-necrosis factor receptor family, and effector molecules such as perforin and interferon-γ. Vaccine efficacy might be improved by strategies that are designed to modulate the expansion, contraction or memory phases of the T-cell response.