Differential Roles of the mTOR-STAT3 Signaling in Dermal γδ T Cell Effector Function in Skin Inflammation

Abstract

Innate dermal γδ T cells play a critical role in skin homeostasis and inflammation. However, the underlying molecular mechanisms by which these cells are activated and differentiated have not been fully understood. In this study, we show that the mTOR signaling and STAT3 pathways are activated in dermal γδ T cells in response to innate stimuli such as IL-1β and IL-23. Although both mTOC1 and mTOC2 are essential for dermal γδ T cell proliferation, mTOC2 deficiency leads to drastically decreased dermal γδT17 cells. Further studies reveal that the IL-1R-MyD88- mTOR pathway is critical in dermal γδ T cell effector function. It appears that mitochondriamediated oxidative phosphorylation is critical in this process. The absence of mTOC2 in dermal γδ T cells ameliorate skin inflammation in an Imiquimod-induced psoriasis-like model. Interestingly, STAT3 pathway while is critical in dermal Vγ4T17 cell effector function but is not required for dermal Vγ6T17 cells. In addition, transcription factor IRF-4 activation promotes dermal γδ T cell IL-17 production by linking IL-1β and IL-23 signaling. Taken together, our results demonstrate that the mTOR-STAT3 signaling differentially regulates dermal γδ T cell effector function in skin inflammation.