Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia
Fanconi anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) mig...
| Autores: | , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| Repositorio: | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| OAI Identifier: | oai:iibsantpau.fundanetsuite.com:p12284 |
| Acceso en línea: | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=12284 https://ddd.uab.cat/record/277638 |
| Access Level: | acceso abierto |
| Palabra clave: | ATM protein ATR protein CD135 antigen CD16 antigen CD3 antigen CD34 antigen CD4 antigen CD56 antigen CD69 antigen CD8 antigen chek 1 protein Fanconi anemia group A protein formaldehyde hemoglobin hemopoietic growth factor mica protein micb protein mitomycin natural killer cell receptor NKG2A natural killer cell receptor NKG2D protein inhibitor sb 2118078 thrombopoietin ulbp1 protein ulbp2 protein ulbp3 protein ulbp4 protein ulbp5 protein ulbp6 protein unclassified drug ligand natural killer cell lectin like receptor subfamily K adolescent adult animal experiment animal model Article bone marrow CD8+ T lymphocyte cell culture cell function child clinical feature controlled study cytotoxicity DNA damage DNA repair Fanconi anemia female fibroblast genetic complementation hematopoietic stem cell human human cell immune system in vivo study innate immunity male mouse nonhuman preschool child protein expression prote |
| Sumario: | Fanconi anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) might express DNA damage-associated stress molecules such as natural killer group 2 member D ligands (NKG2D-Ls). These ligands could then interact with the activating NKG2D receptor expressed in cytotoxic NK or CD8(+) T cells, which may result in progressive HSPC depletion. Our results indeed demonstrated upregulated levels of NKG2D-Ls in cultured FA fibroblasts and T cells, and these levels were further exacerbated by mitomycin C or formaldehyde. Notably, a high proportion of BM CD34(+) HSPCs from patients with FA also expressed increased levels of NKG2D-Ls, which correlated inversely with the percentage of CD34(+) cells in BM. Remarkably, the reduced clonogenic potential characteristic of FA HSPCs was improved by blocking NKG2D-NKG2D-L interactions. Moreover, the in vivo blockage of these interactions in a BMF FA mouse model ameliorated the anemia in these animals. Our study demonstrates the involvement of NKG2D-NKG2D-L interactions in FA HSPC functionality, suggesting an unexpected role of the immune system in the progressive BMF that is characteristic of FA. |
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