Decreased memory persistence in Piezo1 deficient T cells ameliorates disease progression in autoimmune mouse models

Abstract

Abstract To mount a successful immune response, T cells must successfully (1) migrate from the bloodstream into secondary lymphoid organs (naïve) or inflamed tissue (effector), and (2) form an effective immunological synapse for activation. Although the molecular interactions of these processes have been well described, the emergence of novel biophysical approaches has revealed that both critical processes require mechanosensing. Previously we have demonstrated that the mechanosensitive cation channel, Piezo1, forms a complex with activated integrin LFA-1, an important regulator of T cell migration and T cell receptor-triggered T cell activation. Therefore, we hypothesized that Piezo1 deficiency in T cells would diminish T cell activation and homing.To investigate Piezo1’s role on T cell function, we have generated T cell-specific Piezo1 knockout mice (P1cKO) by crossing Piezo1-floxed mice to CD4-Cre mice. Initial studies in vitro showed that under polarizing conditions P1cKO T cells produce more Th1 and Th17 inflammatory cytokines. However, when challenged with experimental autoimmune encephalomyelitis (EAE) and Graft-vs-Host Disease (GVHD), P1cKO mice showed a significant decrease in disease phenotype. Moreover, adoptive transfer mouse models of EAE show that activated P1cKO T cell transfer fails to establish disease phenotype. Upon further investigation, we found similar numbers of P1cKO T cells at sites of inflammation early in disease, but there was a decreased persistence of effector and central memory P1cKO T cells. Taken together, our data suggests that Piezo1 plays an important in role in the development and maintenance of T cell memory pools, while potentially contributing to T cell activation and migration. This project was supported by grants from the NIH (TL1 TR002549, T32 GM007250, T32 AI089474), the St. Baldrick's Foundation Innovation Fund, the Theresia G. & Stuart F. Kline Family Foundation, and the Karen & Alan Krause Pediatric Immunotherapy Innovation and Education Fund.