Exploring the role of YAP signaling in CD4+ T cell biology

Abstract

Abstract The adaptive immune system’s ability to defend against infections and destroy cancerous cells is highly dependent on T cell proliferation. A long-standing observation through in vitro and in vivo studies is that T cells cluster together during activation and subsequent proliferation. In contrast, the vast majority of other cell types turn off division machinery upon cell-cell contact. The highly conserved Hippo signaling pathway controls for cell size and number through proliferation and apoptosis, thereby making it essential for regulating organ size. At the core of the Hippo cascade is the transcription factor YAP. Upon activation, YAP translocates into the nucleus and binds with transcription enhancer factors (TEADs) to drive transcription of proliferation-related genes. While YAP signaling has been extensively studied in epithelial cells, its role in CD4+ T cell effector function and proliferation remains unexplored. Our data indicates that overall YAP protein levels rises during T cell activation. Interestingly, although YAP activation increases proliferation of epithelial cells, our data suggests that YAP is a negative regulator of cellular proliferation in CD4+ T cells. Upon YAP depletion and then restimulating T cells in vitro, we discovered that the T cells knocked down by YAP exhibited greater proliferation and produced more IL-2 than T cells transduced with control shRNA. In support of this surprising finding, expressing a constitutively active YAP with all five phosphorylation sites mutated (YAP 5SA) in T cells led to decreased proliferation of CD4+ T cells. These results hint at potentially novel functions of YAP and warrants further analysis into how YAP signaling affects T cell proliferation.