ZIA BC 011215 (ZIA) | |||
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Title | Immune Regulatory Roles of Suppressor Of Cytokine Signaling (SOCS) Molecules | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Park, Jung-Hyun | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $200,786 | Project Dates | 10/01/2008 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (50.0%) Cancer (100.0%) Interferon (80.0%) |
Hodgkins disease (10.0%) Leukemia (60.0%) Non Hodgkins Lymphoma (30.0%) |
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Research Type | |||
Normal Functioning Development and Characterization of Model Systems |
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Abstract | |||
Among the SOCS family members, SOCS1, SOCS3 and Cish are molecules already known to be involved in modulating cytokine response in T cells. In this study, we have additionally identified SOCS4 as a new SOCS family member to play a role in T cell immunity, and thus we are currently focusing on the expression, regulation and function of SOCS1, SOCS3, Cish and also SOCS4. SOCS1 is highly expressed in immature DP thymocytes to suppress cytokine signaling in pre-selection thymocytes. Suppression of cytokine signaling is a critical mechanism to prevent survival of thymocytes which have failed to get positively selected. On the other hand, cytokine signaling is necessary to provide survival of mature thymocytes and also to direct CD8 lineage choice during CD4/CD8 lineage commitment. In fact, intrathymic cytokine signaling induces expression of the CD8 lineage specifying factor Runx3, and desensitization of cytokine receptor signaling is critical to suppress Runx3 expression and to promote CD4 lineage differentiation. As a potential mechanism to suppress cytokine signaling during CD4 lineage choice, we assessed expression of SOCS family molecule expression in CD4 single positive (SP) thymocytes. We found that both CD8SP and CD4SP thymocytes expressed SOCS1, SOCS3 and Cish, but that CD4 lineage cells expressed significantly higher levels of SOCS1 and Cish than CD8SP thymocytes. SOCS expression is induced by cytokine signaling, so that SOCS molecule expression during CD8 lineage differentiation is a consequence of intrathymic cytokine signaling. However, it was not clear why CD4SP cells expressed high levels of SOCS molecules, and even at higher levels than CD8SP thymocytes. As such, we wished to know if transcription factors that are specifically expressed in CD4 lineage cells would drive SOCS expression in CD4 cells. ThPOK is a zinc-finger nuclear factor that is specifically expressed in CD4 lineage cells and which is induced by strong/persistent TCR signaling during CD4 lineage differentiation. To examine the scenario that ThPOK would induce SOCS expression to inhibit cytokine signaling and direct CD4 lineage choice, we generated a series of ThPOK-transgenic mice with increasing levels of transgenic ThPOK expression. We found that increased ThPOK expression resulted in increased SOCS1, SOCS3 and Cish expression in CD4 T cells. We further identified that ThPOK directly induced SOCS1 transcription in luciferase reporter assays and in ThPOK-transgenic SOCS1 reporter mice. Importantly, ThPOK function was dependent on SOCS1 expression because CD4 lineage redirection by ThPOK was impaired in SOCS1-deficient ThPOK transgenic mice. Reciprocally, transgenic expression of SOCS1 was sufficient to generate CD4 T cells in the absence of ThPOK expression, indicating that the major function of ThPOK is to induce expression of SOCS1. In sum, these data reveal a novel role for SOCS in T cells, revealing that SOCS1 and potentially other SOCS molecules are directly involved in CD4/CD8 lineage decision in the thymus. Because of its potential redundancy with SOCS1, we also proceeded with experiments addressing the role of SOCS3 in T cells. SOCS3 is highly expressed in thymocytes, but only induced to high levels in mature T cells by cytokine stimulation. To understand the downstream effect of SOCS3 under steady state conditions, we generated SOCS3 transgenic (SOCS3 Tg) mice under the control of the human CD2 mini-cassette. While overall T cell development in these mice was comparable to wildtype mice, interestingly, we found that SOCS3 Tg mice had a selective loss (~ 50% reduction) of CD8SP thymocytes and peripheral CD8 T cells. SOCS3 overexpression potently suppressed IL-6-induced STAT3 activation but only modestly suppressed IL-7-indcued STAT5 phosphorylation. These results suggest a cytokine-specific effect of SOCS3 which we are currently investigating with a broader panel of different cytokines. Based on recent findings on IL-17-secreting CD4+ T cells" |