title: CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death.
abstract: 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.
authors.affiliation: Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, California 92121, USA.
authors.forename: Edith M
authors.initials: EM
authors.lastname: Janssen
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Droin
authors.forename: Edward E
authors.initials: EE
authors.lastname: Lemmens
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pinkoski
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Bensinger
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Ehst
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Griffith
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Schoenberger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D007156:Immunologic Memory / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases