International Immunology Advance Access originally published online on May 15, 2006
International Immunology 2006 18(7):1043-1054; doi:10.1093/intimm/dxl038
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Defective cell cycle induction by IL-2 in naive T-cells antigen stimulated in the presence of refractory T-lymphocytes
1 Department of Hematology and Oncology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA
2 Department of Pathology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA
Correspondence to: T. L. Geiger; E-mail: terrence.geiger{at}stjude.org
CD4+ T cells enter a transient refractory period after stimulation. Upon re-stimulation the refractory cells produce little IL-2 and show diminished proliferation. We previously demonstrated that refractory T cells can also, like anergic and CD4+CD25+ regulatory T cells, suppress in trans the proliferation of antigen-stimulated naive T cells. The suppressed T cells up-regulate high-affinity IL-2R but do not produce IL-2. This IL-2 deficit could potentially explain the proliferation failure, but does not appear to do so. Supplementation of refractory-naive co-cultures with exogenous IL-2 fails to alleviate both the proliferation suppression and IL-2 production defects. This does not result from a failure of IL-2 to stimulate its receptor. Proximal IL-2 signaling into suppressed T cells through STAT5 and Akt is intact. However, refractory cell-co-cultured T cells fail to up-regulate cyclins and c-myc and incompletely down-regulate p27kip1 in response to IL-2, and the downstream consequences of this signaling are therefore dissociated. IL-2 signaling is not fully disabled as IL-2 up-regulates the anti-apoptotic protein Bcl-xL to control levels. This up-regulation correlates with enhanced survival of refractory cell-co-cultured T cells placed in IL-2 when compared with cells cultured without IL-2. Thus, refractory T cells are able to suppress naive T-cell proliferative responses in part by blocking both IL-2 production and the mitogenic but not anti-apoptotic effects of IL-2. These results have implications for how activation-refractory T cells may influence nascent immune responses.
Keywords: apoptosis, cytokine, proliferation, signal transduction, suppression, T-cell
Transmitting editor: R. A. Flavell
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