Suppressor of cytokine signalling 3 is crucial for interleukin‐7 receptor re‐expression after T‐cell activation and interleukin‐7 dependent proliferation

SOCS3 is a crucial feedback inhibitor of several cytokine pathways with potential regulatory functions during T cell receptor activation. A role of SOCS3 in IL‐7‐dependent homeostatic mechanisms has been assumed but the underlying mechanisms remain unclear. We investigated the role of SOCS3 in IL‐7 receptor α‐chain (IL‐7Rα) expression and IL‐7 effects on activated human CD4+ T cells. SOCS3 expression modulation by lentiviral transduction combined with T cell phenotyping, receptor signalling analysis, and a novel competitive in vitro assay were applied. Time course analyses following T‐cell activation showed IL‐7Rα re‐expression after initial down‐regulation that was accompanied by increased SOCS3 expression starting on day 2. T cells with low SOCS3 expression (SOCS3kd) had decreased IL‐7Rα levels due to impaired re‐expression. SOCS3 mediated effects on IL‐7Rα were not affected by recombinant IL‐7 or blocking of IL‐2. We found no evidence for SOCS3 effects on IL7RA transcriptional regulation. Functionally, SOCS3kd T cells showed decreased IL‐7‐dependent proliferation as compared to vector control T cells under competitive in vitro conditions. This impaired IL‐7 response of SOCS3kd T cells was accompanied by decreased STAT5 phosphorylation late during IL‐7 signalling. We identified a novel SOCS3 function in IL‐7Rα regulation during T‐cell activation with crucial implications for IL‐7‐dependent mechanisms.