title: Defective cell cycle induction by IL-2 in naive T-cells antigen stimulated in the presence of refractory T-lymphocytes.
abstract: 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.
authors.affiliation: Department of Hematology and Oncology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Inaba
authors.forename: Terrence L
authors.initials: TL
authors.lastname: Geiger
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002453:Cell Cycle / Q000276:immunology*; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000187:drug effects / Q000276:immunology; D018920:Coculture Techniques; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000276:immunology / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt / Q000276:immunology / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000276:immunology*; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D051020:bcl-X Protein / Q000276:immunology
chemical_list: D000941:Antigens; C493961:Cdkn1b protein, mouse; D016213:Cyclins; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D051020:bcl-X Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051058:Oncogene Protein v-akt