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Suppressor of Cytokine Signaling 2 Negatively Regulates NK Cell Differentiation by Inhibiting JAK2 Activity

View Article: PubMed Central - PubMed

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.

No MeSH data available.


The increase of NK cells in SOCS2−/− mice.(A) Phenotypes of CD3−NK1.1+ cells from the BM were determined by two-color flow cytometric analysis using indicated antibodies. The fluorescence intensity was analyzed from the gated lymphocyte population of WT and SOCS2−/− mice. The numbers indicate the percentages of cells in the gated regions. (B,C) Bar graphs show the frequency (B) and the numbers of NK cells in total BM cells (C). The results are representative of at least two independent experiments with similar results. (D) Dot plots indicate the percentage of gated CD3−NK1.1+ cells in the SP. (E,F) Bar graphs show the frequency (E) and the numbers of NK cells in total splenocytes (F). n = 3–4 mice per group. *p < 0.05, **p < 0.01, and ***p < 0.001 (error bars, mean ± SD). Data are representative of at least three independent experiments.
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f1: The increase of NK cells in SOCS2−/− mice.(A) Phenotypes of CD3−NK1.1+ cells from the BM were determined by two-color flow cytometric analysis using indicated antibodies. The fluorescence intensity was analyzed from the gated lymphocyte population of WT and SOCS2−/− mice. The numbers indicate the percentages of cells in the gated regions. (B,C) Bar graphs show the frequency (B) and the numbers of NK cells in total BM cells (C). The results are representative of at least two independent experiments with similar results. (D) Dot plots indicate the percentage of gated CD3−NK1.1+ cells in the SP. (E,F) Bar graphs show the frequency (E) and the numbers of NK cells in total splenocytes (F). n = 3–4 mice per group. *p < 0.05, **p < 0.01, and ***p < 0.001 (error bars, mean ± SD). Data are representative of at least three independent experiments.

Mentions: To investigate the effects of SOCS2 on NK cell development, we analyzed the frequencies and numbers of lymphocytes in the bone marrow (BM) and spleen (SP) of wild-type (WT) or SOCS2−/− mice. Previous studies have shown that there are no significant differences between T- and B-lymphoid, myeloid and erythroid cell populations in SOCS2−/− mice27. Consistent with previous studies, no substantial differences in the population of T, B, and myeloid cells were detected between WT and SOCS2−/− mice (Table S1). However, interestingly, the frequency and number of NK cells in SOCS2−/− mice were increased in the BM (Fig. 1A–C) and SP (Fig. 1D–F). These data suggest that the loss of SOCS2 may be associated with enhanced NK cell development.


Suppressor of Cytokine Signaling 2 Negatively Regulates NK Cell Differentiation by Inhibiting JAK2 Activity
The increase of NK cells in SOCS2−/− mice.(A) Phenotypes of CD3−NK1.1+ cells from the BM were determined by two-color flow cytometric analysis using indicated antibodies. The fluorescence intensity was analyzed from the gated lymphocyte population of WT and SOCS2−/− mice. The numbers indicate the percentages of cells in the gated regions. (B,C) Bar graphs show the frequency (B) and the numbers of NK cells in total BM cells (C). The results are representative of at least two independent experiments with similar results. (D) Dot plots indicate the percentage of gated CD3−NK1.1+ cells in the SP. (E,F) Bar graphs show the frequency (E) and the numbers of NK cells in total splenocytes (F). n = 3–4 mice per group. *p < 0.05, **p < 0.01, and ***p < 0.001 (error bars, mean ± SD). Data are representative of at least three independent experiments.
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Related In: Results  -  Collection

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f1: The increase of NK cells in SOCS2−/− mice.(A) Phenotypes of CD3−NK1.1+ cells from the BM were determined by two-color flow cytometric analysis using indicated antibodies. The fluorescence intensity was analyzed from the gated lymphocyte population of WT and SOCS2−/− mice. The numbers indicate the percentages of cells in the gated regions. (B,C) Bar graphs show the frequency (B) and the numbers of NK cells in total BM cells (C). The results are representative of at least two independent experiments with similar results. (D) Dot plots indicate the percentage of gated CD3−NK1.1+ cells in the SP. (E,F) Bar graphs show the frequency (E) and the numbers of NK cells in total splenocytes (F). n = 3–4 mice per group. *p < 0.05, **p < 0.01, and ***p < 0.001 (error bars, mean ± SD). Data are representative of at least three independent experiments.
Mentions: To investigate the effects of SOCS2 on NK cell development, we analyzed the frequencies and numbers of lymphocytes in the bone marrow (BM) and spleen (SP) of wild-type (WT) or SOCS2−/− mice. Previous studies have shown that there are no significant differences between T- and B-lymphoid, myeloid and erythroid cell populations in SOCS2−/− mice27. Consistent with previous studies, no substantial differences in the population of T, B, and myeloid cells were detected between WT and SOCS2−/− mice (Table S1). However, interestingly, the frequency and number of NK cells in SOCS2−/− mice were increased in the BM (Fig. 1A–C) and SP (Fig. 1D–F). These data suggest that the loss of SOCS2 may be associated with enhanced NK cell development.

View Article: PubMed Central - PubMed

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&minus;/&minus; 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&minus;/&minus; HSCs. We found that SOCS2 could inhibit Janus kinase 2 (JAK2) activity and JAK2-STAT5 signaling pathways via direct interaction with JAK2. Furthermore, SOCS2&minus;/&minus; 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.

No MeSH data available.