A central component of peripheral immune tolerance is Foxp3[+] regulatory T cells (Tregs). Tregs are indispensable for the prevention of autoimmune diseases, but also serve as a major hurdle to tumor immunity and immunotherapy. IL-2 is considered a major regulator for controlling the homeostasis and more recently, lineage stability, of Tregs by signaling through STAT5. Recent studies have also discovered a highly suppressive p-STAT5[+] Treg subpopulation that is critical for the suppression of autoreactive T cells and incipient autoimmunity. Of note, low-dose IL-2 specifically activates Tregs to ameliorate autoimmune diseases in murine models and clinical trials, and there is a growing interest in exploring this new therapeutic strategy. Unlike conventional T cells, Tregs are normally kept in a state of partial IL-2 deficiency due to, in part, Foxp3-dependent repression of IL-2 production and are therefore indexed to a low IL-2 signaling threshold. Additionally, Tregs show a predominant requirement of STAT5 activity due to their low PI3K and MAPK activities downstream of IL-2R. Mechanisms underlying Treg-specific regulation of IL-2 and STAT5 signaling remain uncertain. Through a kinase inhibitor screen, we identified Mst1, a core kinase in Hippo signaling, as a novel IL-2 signal sensor to amplify STAT5 activation in Tregs but not conventional T cells. We therefore hypothesize that Hippo kinases selectively sense and amplify IL-2R?STAT5 signaling to adapt Tregs to a proper IL-2 signaling threshold, thereby maintaining a stable Treg population and regulatory activity.
Aim 1. Establish Mst1?STAT5 axis in Tregs under homeostasis and activation in vivo.
Aim 2. How does Hippo/Mst1 signal in Tregs? Aim 3. Define and reconstruct IL-2-dependent signaling circuits in Tregs. We predict our studies will establish a new paradigm in Treg biology and immune regulation, as well as new mechanisms of Hippo signaling, with the potential to translate into innovative strategies to target autoimmunity and cancer.
Statement Regulatory T cells (Tregs) are indispensable for the establishment of immune tolerance and the prevention of autoimmune diseases, but also serve as a major hurdle to tumor immunity and immunotherapy. IL-2 is considered a major regulator for controlling the homeostasis and lineage stability of Tregs by signaling through STAT5, but mechanisms underlying Treg-specific regulation of IL-2 and STAT5 signaling remain uncertain. Hence, a better understanding of the immune pathways involved in Tregs and IL-2 signaling is essential for our efforts to prevent and treat autoimmune diseases and cancer.
| Shi, Hao; Liu, Chaohong; Tan, Haiyan et al. (2018) Hippo Kinases Mst1 and Mst2 Sense and Amplify IL-2R-STAT5 Signaling in Regulatory T Cells to Establish Stable Regulatory Activity. Immunity 49:899-914.e6 |
