CD4⁺ T-cell help controls CD8⁺ T-cell memory via TRAIL-mediated activation-induced cell death

The 'help' provided by CD4⁺ T lymphocytes during the priming of CD8⁺ T lymphocytes confers a key feature of immune memory: the capacity for autonomous secondary expansion following re-encounter with antigen^1-4. Once primed in the presence of CD4⁺ T cells, 'helped' CD8⁺ T cells acquire the ability to undergo a second round of clonal expansion upon restimulation in the absence of T-cell help. 'Helpless' CD8⁺ T cells that are primed in the absence of CD4⁺ T cells, in contrast, can mediate effector functions such as cytotoxicity and cytokine secretion upon restimulation, but do not undergo a second round of clonal expansion. These disparate responses have features of being 'programmed', that is, guided by signals that are transmitted to naive CD8⁺ T cells during priming, which encode specific fates for their clonal progeny. Here we explore the instructional programme that governs the secondary response of CD8⁺ T cells and find that helpless cells undergo death by activation-induced cell death upon secondary stimulation. This death is mediated by tumour-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Regulation of Trail expression can therefore account for the role of CD4 ⁺ T cells in the generation of CD8⁺ T cell memory and represents a novel mechanism for controlling adaptive immune responses.