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

Janssen, Edith M.
Droin, Nathalie M.
Lemmens, Edward E.
Pinkoski, Michael J.
Bensinger, Steven J.
Ehst, Benjamin D.
Griffith, Thomas S.
Green, Douglas R.
Schoenberger, Stephen P.

¹Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, California 92121, USA
²Department of Microbiology, Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA
³Department of Urology, The Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa 52242, USA

* These authors contributed equally to this work

Received 25 October; accepted 17 December 2004; doi:10.1038/nature03337.

Supplementary Information accompanies the paper on www.nature.com/nature.

Correspondence and requests for materials should be addressed to S.P.S. ([email protected]) or D.R.G. ([email protected]).

Nature 434(7029):p 88-93, March 3, 2005.

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 ofTrailexpression 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.

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

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