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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1006-1012
Interleukin-15 redirects the outcome of a tolerizing T-cell
stimulus from apoptosis to anergy
Hans Dooms,
Tom Van Belle,
Marjory Desmedt,
Pieter Rottiers, and
Johan Grooten
From the Department of Molecular Biology, Molecular Immunology Unit,
Flanders Interuniversity Institute for Biotechnology and Ghent
University, Ghent, Belgium.
Clonal deletion and anergy are 2 mechanisms used by the immune
system to establish peripheral tolerance. In vitro, these mechanisms are induced in T lymphocytes by triggering the T-cell receptor (signal
1) in the absence of costimulation (signal 2). T-cell clones have been
shown either to become anergic or to die in response to signal 1 alone;
yet the factors that govern this choice remain unknown. This study
evaluated the influence of the cytokines interleukin (IL)-2 and IL-15
on the response of the Th1 clone hemagglutinin (T-HA) to signal 1, delivered by stimulation with immobilized anti-CD3 monoclonal antibody
(mAb). The response induced by immobilized anti-CD3 mAb was dependent
on the cytokine milieu; in the presence of IL-2, T-HA cells were
subject to apoptosis, whereas in the presence of IL-15 the cells
remained viable but showed proliferative unresponsiveness. After
release from the anti-CD3 stimulus, the IL-15-rescued T-HA cells
regained responsiveness to IL-2 and IL-15 growth factor activity.
However, they were unable to proliferate when stimulated with their
cognate antigen presented by professional antigen-presenting cells
(signal 1 plus 2) and thus had acquired an anergic phenotype. These
data assign a novel function to the previously reported antiapoptotic
activity of IL-15, namely, the capacity to redirect the T-cell response
to partial stimulation from clonal deletion to anergy. Furthermore,
they emphasize that the cytokine environment can critically influence
the outcome of a tolerizing stimulus.
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