PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease
| Autor: | Hannah K. Choe, Parvathi Ranganathan, Jane E. Jackman, Lotus Neidemire-Colley, Gregory K. Behbehani, Charuta Kale, Raymond D. Devine, Kris Vaddi, Min Wang, Yandi Gao, Yang Zhang, Hong Lin, Natalie E. Sell, Anora Ignaci, Robert A. Baiocchi, Maciej Pietrzak, Katiri Snyder, Nina C. Zitzer, Ramiro Garzon, Maria G. Abad |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Protein-Arginine N-Methyltransferases T-Lymphocytes medicine.medical_treatment T cell Graft vs Host Disease Lymphocyte Activation Proinflammatory cytokine Mice 03 medical and health sciences 0302 clinical medicine Interferon medicine Animals Humans Cytotoxic T cell business.industry Protein arginine methyltransferase 5 Hematopoietic Stem Cell Transplantation General Medicine Cell cycle surgical procedures operative 030104 developmental biology Cytokine medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Interferons business CD8 Research Article medicine.drug |
| Zdroj: | JCI Insight |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.131099 |
| Popis: | Acute graft-versus-host disease (aGVHD) is a T cell–mediated immunological disorder and the leading cause of nonrelapse mortality in patients who receive allogeneic hematopoietic cell transplants. Based on recent observations that protein arginine methyltransferase 5 (PRMT5) and arginine methylation are 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 were upregulated in activated T cells in vitro and in T cells from mice developing aGVHD after allogeneic transplant. PRMT5 expression was also upregulated in T cells of patients who developed aGVHD after allogeneic hematopoietic cell transplant compared with those who did not develop aGVHD. PRMT5 inhibition using a selective small-molecule inhibitor (C220) substantially reduced mouse and human allogeneic T cell proliferation and inflammatory IFN-γ and IL-17 cytokine production. Administration of PRMT5 small-molecule inhibitors substantially improves survival, reducing disease incidence and clinical severity in mouse models of aGVHD without adversely affecting engraftment. Importantly, we show that PRMT5 inhibition retained the beneficial graft-versus-leukemia effect by maintaining cytotoxic CD8(+) T cell responses. Mechanistically, we show that PRMT5 inhibition potently reduced STAT1 phosphorylation as well as transcription of proinflammatory genes, including interferon-stimulated genes and IL-17. Additionally, PRMT5 inhibition deregulates the cell cycle in activated T cells and disrupts signaling by affecting ERK1/2 phosphorylation. Thus, we have identified PRMT5 as a regulator of T cell responses and as a therapeutic target in aGVHD. |
| Databáze: | OpenAIRE |
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