Abstract
Suppressor of cytokine signaling (SOCS) proteins are negative regulators of cytokine responses. Although recent reports have shown regulatory roles for SOCS proteins in innate and adaptive immunity, their roles in natural killer (NK) cell development are largely unknown. Here, we show that SOCS2 is involved in NK cell development. SOCS2−/− mice showed a high frequency of NK cells in the bone marrow and spleen. Knockdown of SOCS2 was associated with enhanced differentiation of NK cells in vitro, and the transplantation of hematopoietic stem cells (HSCs) into congenic mice resulted in enhanced differentiation in SOCS2−/− HSCs. We found that SOCS2 could inhibit Janus kinase 2 (JAK2) activity and JAK2-STAT5 signaling pathways via direct interaction with JAK2. Furthermore, SOCS2−/− mice showed a reduction in lung metastases and an increase in survival following melanoma challenge. Overall, our findings suggest that SOCS2 negatively regulates the development of NK cells by inhibiting JAK2 activity via direct interaction.
Highlights
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in many cellular processes, including development, differentiation, and proliferation[11,12]
We show that SOCS2 functions as a negative regulator of IL-15 signaling in natural killer (NK) cell development and that knockdown of SOCS2 results in increased activity of Janus kinase 2 (JAK2) and STAT5, with a corresponding increase in NK cell differentiation
We showed that IL-15–mediated NK cell differentiation was increased in SOCS2−/− mice (Fig. 2A), SOCS2 did not affect IL-15–mediated NK cell effector functions (Fig. 2E,F)
Summary
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in many cellular processes, including development, differentiation, and proliferation[11,12]. STAT3 negatively regulates NKG2D ligand expression, and inhibiting STAT3 activation enhances NK cell cytotoxicity[14]. STAT4 is highly expressed in resting NK cells and regulates IFN-γproduction upon IL-12 stimulation by activating the T-box transcription factor T-bet[15]. SOCS1 and SOCS3 can bind directly to JAK1, JAK2 and TYK2 to inhibit JAK activity[20,21] These proteins have been demonstrated to regulate CD4+ T cell polarization and plasticity[22]. SOCS2−/− NK cells are hypersensitive to IL-15 treatment and show enhanced IL-15-driven JAK2-STAT5 signaling during NK cell development. We show that SOCS2 inhibits JAK2 activity via direct interaction which is induced by IL-15 treatment. The increase of SOCS2−/− NK cell development is reversed by JAK2 inhibitor treatment in vitro. Our results demonstrate a novel role for SOCS2 in regulating NK cell development
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