Our laboratory investigates immune regulatory mechanism particularly mediated by Foxp3+ regulatory CD4 T cells, a crucial T cell subset playing a central irreplaceable role in immunity.
IL-27 and regulatory T cells
IL-27 is a heterodimeric cytokine composed of p28 (also known as IL-30) and Ebi3 subunits. As it belongs to IL-12 family cytokine, it was initially thought to play a role supporting Th1 immunity. However, IL-27 expresses potent anti-inflammatory roles, inhibiting Th2 and Th17 mediated inflammation. Yet, the cellular mechanisms remain unclear. We previously reported that IL-27 acts on Foxp3+ regulatory T cells to mediate its regulatory functions. Utilizing multiple genetic mouse models where IL-27 production and IL-27 responsiveness are targeted in a cell specific manner, we are currently investigating the primary source of IL-27 in inflammation and the mechanisms by which IL-27 controls inflammatory responses via regulatory T cells.
Lag3 and regulatory T cells
Lymphocyte activation gene 3 (Lag3) is a CD4-like surface molecule expressed on T cells and NK cells following activation. Lag3 is considered a key negative regulator of T cell activation, as its deficiency results in hyperactivation of T cells. Foxp3+ regulatory T cells also highly express Lag3; however, its role in Treg functions remain uncertain. We have previously reported that Lag3 expression on Tregs is induced by IL-27 stimulation and that Lag3 is necessary for Treg suppressive functions to control inflammation in vivo. Treg-specific Lag3 knockout mouse model was developed in the laboratory and are currently being used to investigate in vivo function of Lag3 expressed on Tregs.
We also investigate signaling pathway generated by Lag3 ligation in Tregs. Using biochemical and genetic approaches, we are currently examining the molecular mechanism by which Lag3 controls Treg functions.
Glucocorticoid, miR-342 and immunity
Glucocorticoids have long been used to treat inflammatory disorders more than 70 years. Yet, very little is known about its working mechanism. We recently reported that steroid-induced control of chronic inflammatory responses is mediated via Tregs and that a novel miR-342 plays a key role in this process. In particular, miR-342 targets a metabolism regulator, Rictor, in Tregs. We demonstrated that manipulating miR-342 levels in Tregs results in direct control of Treg metabolism (e.g., oxidative phosphorylation vs. glycolysis) and their functions. Main goal of this project is to uncover functions of novel miR-342 in immunity. We generated animal model in which miR-342 is targeted in a cell type specific manner. These animal models are being used to investigate the underlying mechanisms.