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 antigen1,2,3,4. 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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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.
The authors declare that they have no competing financial interests.
Primary responses of helped and helpless E1B192-200-specific CD8+ T cells in mice genetically modified for various apoptosis related genes. This file shows the enumeration of primary E1B192-200-specific IFN-γ-producing CD8+ T cells for which secondary expansion is depicted in Figure 2b. (PDF 37 kb)
Analysis of secondary expansion in vitro by OVA257-264/Kb tetramers. This file shows secondary expansion of helped and helpless CD8+ T cells from act-mOVA.bm1-immunized as analyzed using OVA257-264/Kb tetramers. (PDF 45 kb)
TRAIL expression in LCMV-specific helpless CD8+ T cells. This file shows the induction of TRAIL mRNA expression by RT-PCR in CD8+ T cells isolated from LCMV-infected mice 14 days after infection that were sorted by flow cytometry using GP33-41/Db tetramers. (PDF 55 kb)
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Janssen, E., Droin, N., Lemmens, E. et al. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434, 88–93 (2005). https://doi.org/10.1038/nature03337
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