Signals required for programming effector and memory development by CD8+ T cells

Matthew F. Mescher, Julie M. Curtsinger, Pujya Agarwal, Kerry A. Casey, Michael Gerner, Christopher D. Hammerbeck, Flavia Popescu, Zhengguo Xiao

Research output: Contribution to journalReview articlepeer-review

480 Scopus citations


Stimulation of naïve CD8+ T cells with antigen and costimulation results in proliferation and weak clonal expansion, but the cells fail to develop effector functions and are tolerant long term. Initiation of the program leading to the strong expansion and development of effector functions and memory requires a third signal that can be provided by interleukin-12 (IL-12) or interferon-α (IFN-α). CD4+ T cells condition dendritic cells (DCs) to effectively present antigen to CD8+ T cells, and this conditioning involves, at least in part, CD40-dependent upregulation of the production of these signal 3 cytokines by the DCs. Upon being fully activated, the cytotoxic T lymphocytes develop activation-induced non-responsiveness (AINR), a form of split anergy characterized by an inability to produce IL-2 to support continued expansion. If antigen remains present, IL-2 provided by CD4+ T cells can reverse AINR to allow further expansion of the effector population and conversion to responsive memory cells following antigen clearance. If IL-2 or potentially other proliferative signals are not available, persistent antigen holds cells in the AINR state and prevents the development of a responsive memory population. Thus, in addition to antigen and costimulation, CD8+ T cells require cytokine signals at distinct stages of the response to be programmed for optimal generation of effector and memory populations.

Original languageEnglish (US)
Pages (from-to)81-92
Number of pages12
JournalImmunological Reviews
StatePublished - Jun 2006


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