Suppressor of Cytokine Signaling-1 Regulates Signaling in Response to Interleukin-2 and Other γc-dependent Cytokines in Peripheral T Cells

Cornish, Ann L.; Chong, Mark M.W.; Davey, Gayle M.; Darwiche, Rima; Nicola, Nicos A.; Hilton, Douglas J.; Kay, Thomas W. H.; Starr, Robyn; Alexander, Warren S.

doi:10.1074/jbc.m303021200

Cited by 115 publications

(82 citation statements)

References 50 publications

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“…Both SOCS1 and SOCS3 appear to play key roles in regulating cytokine signalling in T cells (Brender et al, 2007;Chong et al, 2003;Cornish et al, 2003a;Davey et al, 2005;Fujimoto et al, 2000;Gagnon et al, 2007;Ilangumaran et al, 2003;Ramanathan et al, 2006;Yu et al, 2006). Although the role of SOCS1 in the thymus has been well studied, little is known about the function of SOCS3 during thymopoiesis.…”

Section: Discussionmentioning

confidence: 99%

“…Although the inclusion of IL-7 in cultures promotes proliferation of thymocyte progenitors early in the culture period, high IL-7 levels inhibit differentiation at both the DN2:DN3 and DP stages of development (Balciunaite et al, 2005;DeLuca and Clark, 2002;El Kassar et al, 2004;Huang et al, 2005). Since SOCS1 negatively regulates IL-7 signalling (Chong et al, 2003;Cornish et al, 2003a;Ramanathan et al, 2006;Yu et al, 2006), we wished to investigate whether the block in early thymocyte differentiation in the absence of SOCS1 was due to hypersensitivity to IL-7.…”

Section: Perturbed Thymopoiesis In Vitro In the Absence Of Socs1 And mentioning

confidence: 99%

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Perturbed thymopoiesis in vitro in the absence of suppressor of cytokine signalling 1 and 3

Croom¹,

Izon²,

Chong³

et al. 2008

Molecular Immunology

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Cytokine signals are central to the differentiation of thymocytes and their stepwise progression through defined developmental stages. The intensity and duration of cytokine signals are regulated by the suppressor of cytokine signalling (SOCS) proteins. A clear role for SOCS1 during the later stages of thymopoiesis has been established, but little is known about its role during early thymopoiesis, nor the function of its closest relative, SOCS3. Here, we find that both SOCS1 and SOCS3 are expressed during early thymopoiesis, with expression coincident during the double negative (DN)2 and DN3 stages. We examined thymocyte differentiation in vitro by co-culture of SOCS-deficient bone marrow cells with OP9 cells expressing the Notch ligand Delta-like1 (OP9-DL1). Cells lacking SOCS1 were retarded at the DN3:DN4 transition and appeared unable to differentiate into double positive (DP) thymocytes. Cells lacking both SOCS1 and SOCS3 were more severely affected, and displayed an earlier block in T cell differentiation at DN2, the stage at which expression of SOCS1 and SOCS3 coincides. This indicates that, in addition to their specific roles, SOCS1 and SOCS3 share overlapping roles during thymopoiesis. This is the first demonstration of functional redundancy within the SOCS family, and has uncovered a vital role for SOCS1 and SOCS3 during two important checkpoints in early T cell development.

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Section: Discussionmentioning

confidence: 99%

Section: Perturbed Thymopoiesis In Vitro In the Absence Of Socs1 And mentioning

confidence: 99%

Perturbed thymopoiesis in vitro in the absence of suppressor of cytokine signalling 1 and 3

Croom¹,

Izon²,

Chong³

et al. 2008

Molecular Immunology

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“…SOCS1 is particularly important for T cell homeostasis regulation [12]. For instance, SOCS1 regulates IL-7 and IL-15 functions during T lymphocyte development and homeostasis [18].…”

Section: Discussionmentioning

confidence: 99%

“…The suppressor of cytokine signaling 1 molecule (SOCS1) controls signaling of many cytokines, including IFN-γ, IFN-α, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-15, and IL-21 utilizing a feedback loop mechanism [10][11][12][13][14][15][16][17][18][19]. First, binding of a cytokine to its receptor upregulates expression of SOCS1.…”

Section: Introductionmentioning

confidence: 99%

SOCS1 downregulation in dendritic cells promotes memory T-cell responses

Aldrich

Sanders

Lapteva

et al. 2008

Vaccine

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SOCS1-1 is crucial for control of immune cell cytokine expression, including those cytokines known to enable memory T cell formation and homeostasis. In this study, we found that immunization with SOCS1-downregulated bone marrow-derived dendritic cells generated increased antigen-specific CD8 + T memory cells and antigen-specific responses, as measured by ELISPOT, CTL assays, serum ELISAs, and T-cell proliferation assays. Bone marrow-derived dendritic cells in which SOCS1 was downregulated expressed increased levels of surface IL-15Ra and thymic leukemia (TL) antigen, both of which support memory cell development. This work supports a crucial role for SOCS1 in regulation of dendritic cell-directed generation of memory T cell responses.

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“…The inhibitory effects of SOCS proteins on cytokine signalling have been definitively demonstrated through analyses of mice harboring loss of functional alleles. In the absence of SOCS1 or SOCS3, mice exhibited profound pathologies including multiple haemopoietic and immunological defects as a consequence of prolonged STAT activation Cornish et al 2003;Croker et al 2003;Croker et al 2004;Lang et al 2003;Naka et al 1998;Starr et al 1998;Yasukawa et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Regulation of multiple cytokine signalling pathways by SOCS3 is independent of SOCS2

Kiu¹,

Greenhalgh²,

Thaus³

et al. 2009

GGRF

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Suppressor of cytokine signalling (SOCS) 3 is an essential regulator of cytokine signalling, and in turn its expression is tightly regulated. Data from overexpression studies in cell lines suggest that SOCS2 regulates SOCS3 protein degradation, by forming a molecular bridge to an E3 ubiquitinligase complex. Whether this regulation is relevant in primary cells is unknown. In this study, we utilized Socs2 −/− mice to examine the role of SOCS2 in modulating SOCS3 expression and degradation, and its impact on IL-2 and IL-6 signalling in primary haemopoietic cells. Both biochemical and biological analyses demonstrated unperturbed SOCS3 expression and cytokine signalling in the absence of SOCS2. Our results suggest that SOCS2 is not a physiological regulator of SOCS3 expression and action in primary haemopoietic cells.

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Suppressor of Cytokine Signaling-1 Regulates Signaling in Response to Interleukin-2 and Other γc-dependent Cytokines in Peripheral T Cells

Cited by 115 publications

References 50 publications

Perturbed thymopoiesis in vitro in the absence of suppressor of cytokine signalling 1 and 3

Perturbed thymopoiesis in vitro in the absence of suppressor of cytokine signalling 1 and 3

SOCS1 downregulation in dendritic cells promotes memory T-cell responses

Regulation of multiple cytokine signalling pathways by SOCS3 is independent of SOCS2

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