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.