PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

ABSTRACT: Acute Graft-Versus-Host Disease (aGVHD) is a T cell mediated immunological disorder and the leading cause of non-relapse mortality in patients who receive allogeneic hematopoietic cell transplants. Based on recent observations that PRMT5 and arginine methylation is upregulated in activated memory T cells, we hypothesized that PRMT5 is involved in the pathogenesis of aGVHD. Here, we show that PRMT5 expression and enzymatic activity is upregulated in activated T cells in vitro and in T cells from mice developing aGVHD after allogeneic transplant. PRMT5 inhibition using a selective small-molecule inhibitor (C220) significantly reduces mouse and human allogeneic T cell proliferation and inflammatory IFN-g and IL-17 cytokine production. Administration of PRMT5 small-molecule inhibitors significantly improves survival, reducing disease incidence and clinical severity in mouse models of aGVHD without adversely affecting engraftment. Importantly, we show that PRMT5 inhibition retains the beneficial GVL effect by maintaining cytotoxic CD8 T cell responses. PRMT5 inhibition potently reduces transcription of pro-inflammatory genes including Interferon Stimulated Genes (ISG) and IL-17. PRMT5 inhibition deregulates cell-cycle in activated T cells and disrupts signaling by impacting ERK1/2 phosphorylation. Thus, we have identified PRMT5 as a regulator of T cell responses and as a novel therapeutic target in aGVHD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE145527 | GEO | 2020/05/13

REPOSITORIES: GEO