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 antigen1-4. 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.
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Acknowledgements We thank R. van Beem and E. Sellink for human monocyte and HUVEC isolations, W. Moolenaar, B. Giepmans and L. van Zeijl for A431/Cx43 cells and Cx43 reagents, R. Luiten and H. Spits for T-cell clone (InfA13TGA), W. E. Benckhuijsen for peptide synthesis, E. Mesman and M. Tjin-A-Koeng for immunohistochemistry, K. Jalink for experimental support, and H. Pickersgill, A. Griekspoor and M. Wolkers for critical reading. This work was supported by grants from the Dutch Cancer Society KWF.
Acknowledgements We thank H. Grey for critical evaluation of the manuscript and S. Jameson for providing peptide/MHC tetramers. This work was supported in part by grants from the National Institutes of Health and the American Cancer Society and by a gift from the estate of Wilton N. Chamberlain. This is manuscript number 649 from the La Jolla Institute for Allergy and Immunology.