Piezo1 restrains proinflammatory response but is essential in T cell-mediated immunopathology.

Abstract

Piezo1 is a mechanosensitive, nonselective Ca2+ channel which is broadly expressed in CD4+ T cells. Using lineage-specific Piezo1 knockout mice (Piezo1cKO), we show that loss of Piezo1 in CD4+ T cells significantly increased IFNγ and IL-17 production in vitro under TH1 and TH17 polarizing conditions, respectively. Despite their intrinsic proinflammatory phenotype, Piezo1cKO T cells are incapable of establishing disease in vivo in three separate adoptive transfer (AT) T cell-mediated inflammatory mouse models, including experimental autoimmune encephalomyelitis, inflammatory bowel disease (IBD), and graft versus-host disease. These phenomena coincided with a decreased effector memory (CD44hiCD62Llo) CD4+ T cell pool derived from donor Piezo1cKO T cells, an observation that is related to intrinsic T-cell fitness, as co-transfer IBD mouse model revealed a deficiency in the CD4+ effector memory population derived only from the naïve Piezo1cKO but not co-infused Piezo1WT CD4+ T cell source. Taken together, our results support Piezo1 as restraining proinflammatory T cell differentiation while contributing to the generation and persistence of the effector memory pool during CD4+ T cell-mediated immunopathology.