It is becoming clear that CD4 T cell plasticity is an important aspect of initiating and regulating immune responses. Among the factors that play a critical role in determining T cell differentiative fate is TGF. Recent work has shown that TGF, through its ability to induce the expression of both Foxp3 and ROR?t, is involved in iTreg/Th17 differentiation. Exposure of CD4 T cells to antigen in the presence of TGF alone leads to iTreg development, while the presence of inflammation cytokines (e.g., IL-6) with TGF results in Th17 differentiation. Thus, the ability of TGF to regulate the expression of Foxp3 and ROR?t based on microenvironmental cues, is a key aspect of T cell function. Factors that regulate TGF function are therefore important players in this process. One such factor is the proto-oncogene c-Ski. The Ski gene was first identified as v-Ski, the retroviral oncogene in Sloan-Kettering retroviruses capable of transforming chicken embryo fibroblasts. The cellular homolog, c-Ski, has been shown to be important for several aspects of embryonic development, and Ski- deficiency leads to late embryonic death. Ski functions as a natural inhibitor of the TGF signaling pathway by targeting several downstream signaling events. However, a role for Ski in the immune system has not been determined. Given the important role of TGF in regulating immune responses, a better understanding of Ski in the context of immune development and responses is important. For this work we have generated a mouse strain that contains a conditional knockout allele of Ski, allowing us to delete Ski specifically in T cells. These mice wll allow us to determine the role of Ski in T cell homeostasis and function. With this in mind, the aims of this proposal are: 1. Determine the role of Ski in regulating TGF-mediated effects in CD4 T cells; 2. Determine the role of Ski in regulating T cell homeostasis; 3. Determine the effect of Ski-deficiency on CD4 T cell function.
Identification and characterization of the factors that control the ability of the immune system to distinguish self from non-self is critical to the development of therapeutics for the treatment of autoimmune diseases. This is especially true at mucosal surfaces where the ability to distinguish between harmless environmental factors and pathogens is crucial. The cytokine TGF is intimately involved in this process as it is critical to the differentiation of both regulatory T cells and effector T cells. Maintaining this balance is very important, and identifying other factors that influence these differentiative decisions will shed important light on this process, and define new pathways for potential therapeutic intervention.
| Thompson, Lucas J; Lai, Jen-Feng; Valladao, Andrea C et al. (2016) Conditioning of naive CD4(+) T cells for enhanced peripheral Foxp3 induction by nonspecific bystander inflammation. Nat Immunol 17:297-303 |
