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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 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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Figure 1: Caspase inhibitors restore secondary expansion in helpless CD8+ T cells.
Figure 2: Trail expression prevents secondary expansion of helpless CD8+ T cells.
Figure 3: Trail-mediated defective secondary expansion of LCMV-specific helpless CD8+ T cells.
Figure 4: Suicide and fratricide by helpless CD8+ T-cell-derived Trail.


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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.

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Corresponding authors

Correspondence to Douglas R. Green or Stephen P. Schoenberger.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure S1

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)

Supplementary Figure S2

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)

Supplementary Figure S3

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)

Supplementary Figure Legends (DOC 22 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).

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