Cellular communication in kidney microniches driving alloimmunity

About This Grant

PROJECT SUMMARY Alloreactive T cells initiate effector cell and support alloantibody (alloAb) responses in patients after allogeneic transplantation. Current approaches are not uniformly efficacious in preventing or ameliorating T effector cell and alloAb mediated kidney rejection. Using fate-mapper and reporter strains, we show that Tfh cells in kidney allografts sequentially differentiate through stem-like Tfh progenitor (TfhProg), effector Tfh, and dysfunctional TfhEx stages which is supported by kidney proximal tubule epithelial cells (PTECs). Moreover, kidney PTECs sense and respond to Tfh-induced stimuli leading to local injury. We hypothesize that bidirectional communication between Tfh cells and PTEC provide a feedback loop that exacerbates kidney injury and inflammation leading to graft rejection. In Aim 1, we will identify the kidney microniches promoting Tfh reprogramming in grafts. In Aim 2, we will assess the roles of kidney epithelial-derived signals in Tfh differentiation and reprogramming. In Aim 3, we will assess how Tfh-derived cytokine signals promote PTEC activation and injury. We will pursue these aims using innovative strategies to identify, fate map, and perturb Tfh cell differentiation as well as PTEC pathways in vivo during murine kidney transplantation. We will combine these innovative tools with human kidney biopsy and gene perturbation studies to validate findings. The expected outcome of these studies is to determine the fundamental role of Tfh cells in kidney allograft injury along with precise mechanisms used by Tfh and PTEC to promote disease. These studies are significant because they will provide new strategies to prevent and treat kidney allograft rejection.