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IL-2 Unresponsiveness in Anergic CD4⁺ T Cells Is Due to Defective Signaling Through the Common -Chain of the IL-2 Receptor¹

Susanna Grundström^2,*, Mikael Dohlsten and Anette Sundstedt

^* Active Biotech Research Center, Lund, Sweden; and Department of Cell and Molecular Biology, Section for Tumor Immunology, Lund University, Lund, Sweden

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 -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 -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 -chain of the IL-2R.

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