The Journal of Experimental Medicine
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Published 5 May 2003. doi:10.1084/jem.20021910
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© Rockefeller University Press, 0022-1007/2003/5/1141 $5.00
The Journal of Experimental Medicine, Volume 197, Number 9, 1141-1151

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 and Matthew F. Mescher

Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455

Address correspondence to Matthew F. Mescher, Dept. of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota, Mayo Mail Code 334, 420 Delaware St. S.E., Minneapolis, MN 55455. Phone: 612-626-2368; Fax: 612-625-2199; E-mail: mesch001{at}tc.umn.edu

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-{gamma} 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.

Key Words: antigens • cell division • immune tolerance • interleukin-12 • lymphocytes


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