Interleukin-15 redirects the outcome of a tolerizing T-cell stimulus from apoptosis to anergy.
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.
Department of Molecular Biology, Molecular Immunology Unit, Flanders Interuniversity Institute for Biotechnology and Ghent University, Belgium.
H
H
Dooms
T
T
Van Belle
M
M
Desmedt
P
P
Rottiers
J
J
Grooten
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D005260:Female; D019409:Interleukin-15 / Q000276:immunology* / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000473:pathology* / Q000502:physiology*
D017252:CD3 Complex; D019409:Interleukin-15; D007376:Interleukin-2