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

Nature. 2005 Mar 3;434(7029):88-93. doi: 10.1038/nature03337.


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. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Apoptosis* / genetics
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cells, Cultured
  • Immunologic Memory / immunology*
  • Lymphocyte Activation / immunology*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*


  • Apoptosis Regulatory Proteins
  • Caspase Inhibitors
  • Membrane Glycoproteins
  • RNA, Messenger
  • TNF-Related Apoptosis-Inducing Ligand
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Caspases