Signal 3 determines tolerance versus full activation of naive CD8 T cells: Dissociating proliferation and development of effector function

Julie M. Curtsinger, Debra C. Lins, Matthew F. Mescher

Research output: Contribution to journalArticlepeer-review

370 Scopus citations

Abstract

Activation of naive CD8 T cells to undergo clonal expansion and develop effector function requires three signals: (a) Ag, (b) costimulation, and (c) IL-12 or adjuvant. The requirement for the third signal to stimulate Ag-dependent proliferation is variable, making the greatest contribution when Ag levels are low. At high Ag levels, extensive proliferation can occur in vitro or in vivo in the absence of a third signal. However, despite having undergone the same number of divisions, cells that expand in the absence of a third signal fail to develop cytolytic effector function. Thus, proliferation and development of cytolytic function can be fully uncoupled. Furthermore, these cells are rendered functionally tolerant in vivo, in that subsequent restimulation with a potent stimulus results in limited clonal expansion, impaired IFN-γ production, and no cytolytic function. Thus, the presence or absence of the third signal appears to be a critical variable in determining whether stimulation by Ag results in tolerance versus development of effector function and establishment of a responsive memory population.

Original languageEnglish (US)
Pages (from-to)1141-1151
Number of pages11
JournalJournal of Experimental Medicine
Volume197
Issue number9
DOIs
StatePublished - May 5 2003

Keywords

  • Antigens
  • Cell division
  • Immune tolerance
  • Interleukin-12
  • Lymphocytes

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