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 | $215,072 | Project Dates | 01/01/2008 - 00/00/0000 |
Fiscal Year | 2015 | 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 | |||
We have focused our efforts of understanding the role of SOCS family molecules into four members, namely SOCS1, SOCS3, SOCS4 and Cish. SOCS1 is highly expressed in immature thymocytes and necessary to suppress cytokine signaling in pre-selection thymocytes. During CD4/CD8 lineage commitment in the thymus, sustained and increasing amounts of SOCS1 expression is necessary for stringent CD4 lineage choice. However, it has not been known what controls SOCS1 expression during thymocyte differentiation. Interestingly, we found that SOCS1 is a direct downstream target of the transcription factor ThPOK. The zinc-finger nuclear factor ThPOK is specifically expressed in CD4 lineage cells and is induced by strong/persistent TCR signaling during CD4 lineage differentiation. ThPOK is considered to be a master regulator of CD4 lineage fate because its expression is both necessary and sufficient to impose CD4 lineage fate on positively selected thymocytes. However, why ThPOK is required for CD4 lineage choice has not been clear. Here we show that ThPOK is required for CD4 lineage choice because it upregulates transcription and expression of SOCS1, and other SOCS family molecules, including SOCS3 and Cish. To test the idea that ThPOK induces SOCS expression to direct CD4 lineage choice, we generated a series of ThPOK-transgenic mice with increasing levels of transgenic ThPOK expression. Transgenic ThPOK was functional because it redirected MHCI-selected thymocytes into CD4 lineage T cells. Interestingly, 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. ThPOK function was dependent on SOCS1 expression because CD4 lineage redirection by ThPOK was impaired when SOCS1 was absent. Reciprocally, enforced expression of SOCS1 was sufficient to generate CD4 T cells in the absence of ThPOK, indicating that a major role of ThPOK in CD4/CD8 lineage choice is to induce expression of SOCS genes. In sum, these data demonstrated a new circuitry of ThPOK and SOCS family molecules, and they revealed that SOCS1 and potentially other SOCS molecules are directly involved in CD4/CD8 lineage decision in the thymus. In addition to SOCS1, SOCS3 is also highly expressed in pre-selection thymocytes. SOCS3 expression was also upregulated by ThPOK during thymocyte differentiation. To further examine the role of SOCS3 in T cell development, we generated SOCS3 transgenic mice where the transgene is driven by a human CD2 mini-cassette. Overall T cell development in these mice was comparable to wildtype mice, except for a selective loss (~ 50% reduction) of CD8SP thymocytes and peripheral CD8 T cells. These data are in agreement with a cytokine requirement for CD8 lineage differentiation, and they demonstrate that SOCS3 also plays a role in CD4/CD8 lineage choice. Interestingly, the inhibitory effect on CD8 lineage differentiation was much milder than in SOCS1 transgenic mice which have a near complete block in CD8 thymocyte generation. Indeed, SOCS3 overexpression potently suppressed IL-6-induced STAT3 activation in T cells, but only modestly suppressed IL-7-induced STAT5 phosphorylation. Of note, intrathymic IL-7 signaling is considered the most important cytokine signal for CD8 lineage choice. Collectively, these results suggest a cytokine-specific effect of SOCS3 which we are currently investigating with a broader panel of different cytokines. In addition to SOCS1 and SOCS3, we further identified SOCS4 as another SOCS family member that is highly expressed in immature thymocytes. To address its role in T cell development, we generated a T cell-specific SOCS4 transgenic mouse. We found that SOCS4 overexpression suppresses T cell development and impaired positive selection of HY-TCR transgenic thymocytes. We are currently in the process of further analyzing the molecular basis for this observation and how SOCS4 |