Foxp3+ regulatory T cells (Tregs) are fundamental in regulating Th2-mediated immunologic diseases at mucosal interfaces including the respiratory tract. Fosp3+Tregs are dysregulated in human airway inflammatory diseases, highlighting their pivotal roles in regulating homeostasis of immune system. However, the mechanism by which Tregs control Th2 immune responses at the mucosal interfaces is not completely understood. Previously, we reported that Pak2, a serine/threonine kinase regulating actin cytoskeleton following T cell receptor stimulation, has a critical role in Treg development and peripheral immune tolerance. To further determine the role of Pak2 in Tregs, we generated a novel mouse model that deletes Pak2 in the Foxp3+Treg lineage. Surprisingly, loss of Pak2 in Tregs resulted in exaggerated Th2-mediated immune responses accompanied by massive immune cell infiltration to the lung and skin. Expression of Foxp3 was reduced in Pak2-deficient Foxp3+Tregs, suggesting that stability of Foxp3 was hindered. Surprisingly, Pak2-deficient Foxp3+Tregs induced expression cytokines such as IL-4 and IFNg, which normally are suppressed in Foxp3+Tregs, implicating reduced stability of Foxp3 results in loss of Treg identity and makes them plastic to become cytokine-producing hybrid Tregs. It is not clear how loss of Pak2 in Tregs regulates these processes.
|Effective start/end date||8/1/16 → 7/31/18|
- Amgen, Inc. (Agmt 09/22/16)