We are currently focusing on the role of three SOCS family members, i.e. SOCS4, CISH and SOCS3. For all three molecules, we have generated new reagents that allow us to study their biological functions in vivo. Previously, we generated a T cell specific SOCS4 transgenic mouse, which we have now used to assess the role of SOCS4 in T cell development. To do so, we introduced a TCR transgene into SOCS4 transgenic mice and then made these mice deficient for RAG-2 so that the only TCR that is expressed is derived from the TCR transgene. Remarkably, we found that fixing the TCR specificity exaggerated the effect of SOCS4. In AND TCR transgenic RAG-deficient SOCS4 transgenic mice (AND.RAG.SOCS4), we found that immature DP thymocytes were distinct to AND.RAG deficient mice regarding their TCR levels and TCR reactivity. Thus, even as SOCS4 was originally identified as a potential suppressor of cytokine signaling, here we report a new role for SOCS4 in TCR signaling. Notably, transgenic SOCS4 did not affect cytokine signaling as we failed to observe any difference in IL-7 downstream signaling in thymocytes and mature T cells. Curiously, SOCS4 transgenic mice have a much smaller thymus and a partial block in the immature DN thymocyte stage leaving the possibility open of impairments in other downstream signaling pathways such as PI-3K or MAPK activation being the target of SOCS4-mediated cytokine suppression. Our current observation that SOCS4 might intersect with the TCR signaling pathway now suggest a much broader role for SOCS molecules than in suppression of cytokine signaling, which might account for impaired thymocyte development independent of cytokines.In parallel to SOCS4, we generated SOCS3 transgenic mice to study SOCS3 effect in T cell development and reactivity. While total thymocyte numbers were not affected, we found that SOCS3 Tg mice had selectively reduced percentage and numbers ( 50% reduction) of CD8SP thymocytes and peripheral CD8 T cells. Interestingly, SOCS3 overexpression suppressed IL-6 signaling but not IL-7-indcued STAT5 phosphorylation suggesting a cytokine-specific effect of SOCS3. Furthermore, when assessing SOCS3 SOCS1 double transgenic mice, we found that SOCS1 and SOCS3 have partially overlapping but also non-redundant functions in T cells. Consequently, we aim to study their roles using a series of inflammatory and autoimmune mouse models. Specifically, SOCS3 has been previously shown to suppress STAT3-dependent signaling. Based on recent findings on interleukin-17-secreting CD4+ T cells (Th17 cells) and their requirement for STAT3 signaling, we aim to utilize SOCS3 transgenic mice to test the role of SOCS3 in T cell function using autoimmune disease models such as experimental autoimmune encephalomyelitis (EAE) in context of Th17 cell differentiation and activation.Additionally, we are focusing our research on CISH as we found that CISH expression was induced in TCR stimulated cells which suggest a potential feedback mechanism for TCR and cytokine signaling. CISH is known to inhibit STAT5 phosphorylation which in turn is critical for thymocyte development and T cell activation. To understand the in vivo requirement for CISH, we generated CISH deficient mice using gene trap technology and also generated CISH transgenic mice using by expressing a FLAG-tagged CISH cDNA under the control of the human CD2 mini-cassette. We are currently in the process of analyzing the T cell function of these mice. Altogether, we are investigating the functions of three SOCS family members, i.e. SOCS4, SOCS3 and CISH. Using a panel of transgenic mice and a series of in vitro studies, we are in the process of determining the biological role of regulating cytokine responsiveness by SOCS family molecules in T cell activation and homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011215-04
Application #
8553048
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2012
Total Cost
$322,692
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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