We have been focusing on the role of three SOCS family members, i.e. SOCS4, CISH and SOCS3. We targeted these molecules because they are highly expressed in thymocytes or in activated T cells but their role in T cell function has remained not well known. To assess their biological significance, we have generated new reagents that allowed 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 and T cell activation. We introduced a HY TCR transgene into SOCS4 transgenic mice and then made these mice additionally deficient for RAG-2 so that the only TCR that is expressed is derived from the TCR transgene. Remarkably, fixing the TCR specificity exacerbated the effect of SCSO4 overexpression and revealed a role for SOCS4 in thymocyte positive selection. Specifically, we found that T cell maturation and homeostasis were impaired in HY SOCS4 transgenic female mice, and that SOCS4 affected TCR levels and TCR reactivity in thymocytes. Thus, even as SOCS4 was originally identified as a potential suppressor of cytokine signaling, we now report a new role for SOCS4 in TCR signaling. Importantly, we performed a series of biochemical studies and were able to identify direct interaction of SOCS4 with the TCR signaling complex. We are currently in the process of further pursuing this observation. Interestingly, 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. Our finding that SOCS4 intersects with the TCR signaling pathway suggests a much broader role for SOCS molecules than in suppression of cytokine signaling. In parallel to our studies on SOCS4, we also proceeded with experiments addressing the role of SOCS3, because SOCS3 is highly expressed in thymocytes and because SOCS3 expression is induced upon cytokine signaling. To this end, 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. Whether SOCS3 also plays a role in TCR signaling, such as SOCS4, is a pending question that we aim to address in future studies. Finally, we were also interested in understanding the role of Cish, because we found that CISH expression was induced in TCR stimulated cells. These data suggest a role for Cish as a potential feedback mechanism for TCR and cytokine signaling. In agreement, 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 by expressing a FLAG-tagged Cish cDNA under the control of the human CD2 mini-cassette. We have been analyzing the T cell function of these mice, but did not find a major effect. However, recent reports suggested that Cish could negatively regulate differentiation of Th2 and Th9 subsets by inhibiting activation of STAT4, STAT5 and STAT6. We plan to address these points using our reagents.

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Luckey, Megan A; Kimura, Motoko Y; Waickman, Adam T et al. (2014) The transcription factor ThPOK suppresses Runx3 and imposes CD4(+) lineage fate by inducing the SOCS suppressors of cytokine signaling. Nat Immunol 15:638-45
Kimura, Motoko Y; Pobezinsky, Leonid A; Guinter, Terry I et al. (2013) IL-7 signaling must be intermittent, not continuous, during CD8⁺ T cell homeostasis to promote cell survival instead of cell death. Nat Immunol 14:143-51
Hasley, Rebecca B; Hong, Changwan; Li, Wenqing et al. (2013) HIV immune activation drives increased Eomes expression in memory CD8 T cells in association with transcriptional downregulation of CD127. AIDS 27:1867-77
Tinsley, Kevin W; Hong, Changwan; Luckey, Megan A et al. (2013) Ikaros is required to survive positive selection and to maintain clonal diversity during T-cell development in the thymus. Blood 122:2358-68
Hong, Changwan; Nam, Anna S; Keller, Hilary R et al. (2013) Interleukin-6 expands homeostatic space for peripheral T cells. Cytokine 64:532-40
Linowes, Brett A; Ligons, Davinna L; Nam, Anna S et al. (2013) Pim1 permits generation and survival of CD4+ T cells in the absence of γc cytokine receptor signaling. Eur J Immunol 43:2283-94
Luckey, Megan A; Park, Jung-Hyun (2013) γc Cytokine signaling: graduate school in thymic education. Blood 121:4-6
Um, Jee-Hyun; Brown, Alexandra L; Singh, Samarendra K et al. (2013) Metabolic sensor AMPK directly phosphorylates RAG1 protein and regulates V(D)J recombination. Proc Natl Acad Sci U S A 110:9873-8
Callen, Elsa; Faryabi, Robert B; Luckey, Megan et al. (2012) The DNA damage- and transcription-associated protein paxip1 controls thymocyte development and emigration. Immunity 37:971-85
McCaughtry, Tom M; Etzensperger, Ruth; Alag, Amala et al. (2012) Conditional deletion of cytokine receptor chains reveals that IL-7 and IL-15 specify CD8 cytotoxic lineage fate in the thymus. J Exp Med 209:2263-76

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