IL-2 unresponsiveness in anergic CD4+ T cells is due to defective signaling through the common gamma-chain of the IL-2 receptor.
Repeated administration of the superantigen staphylococcal enterotoxin A to mice transduces a state of anergy in the CD4+ T cell compartment, characterized by inhibition of IL-2 production and clonal expansion in vivo. In contrast to what has been reported on anergic T cell clones in vitro, culture of in vivo anergized CD4+ T cells in the presence of exogenous IL-2 did not overcome the block in responsiveness. In this study, we demonstrate that CD4+ T cells from mice anergized with staphylococcal enterotoxin A also exhibit a reduced proliferative capacity in response to IL-7 and IL-15, cytokines that share a common gamma-chain with the IL-2R. Flow-cytometric analysis revealed only modest changes in the expression of the different IL-2R chains. In a number of experiments, our results also provide evidence that excludes a major role of the IL-2R alpha-chain in this system. According to these results, the inability of anergic cells to respond to IL-2 is not mainly due to a down-regulation of the high affinity IL-2R, but to a perturbation in intracellular signaling. Our study confirmed that the activation and tyrosine phosphorylation of Janus-associated kinase 3 and STAT5 were considerably weaker after anergy induction. Moreover, anergic CD4+ T cells showed significantly reduced DNA-binding ability to STAT5-specific elements. Taken together, we suggest that the observed IL-2 unresponsiveness in anergic CD4+ T cells could be due to a defect in signaling through the common gamma-chain of the IL-2R.
Grundström
S
S
Active Biotech Research Center, Lund, Sweden. susanna.grundstrom@activebiotech.com
Dohlsten
M
M
Sundstedt
A
A
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004768:Enterotoxins / Q000008:administration & dosage; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D007275:Injections, Intravenous; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D053616:Janus Kinase 3; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism
D004268:DNA-Binding Proteins; D004768:Enterotoxins; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D008894:Milk Proteins; D020033:Protein Isoforms; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C026066:enterotoxin A, Staphylococcal; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3