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Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia
José A. Casado, … , Paula Rio, Juan A. Bueren
José A. Casado, … , Paula Rio, Juan A. Bueren
Published June 7, 2022
Citation Information: J Clin Invest. 2022;132(15):e142842. https://doi.org/10.1172/JCI142842.
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Research Article Immunology Article has an altmetric score of 44

Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia

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Abstract

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.

Authors

José A. Casado, Antonio Valeri, Rebeca Sanchez-Domínguez, Paula Vela, Andrea López, Susana Navarro, Omaira Alberquilla, Helmut Hanenberg, Roser Pujol, José-Carlos Segovia, Jordi Minguillón, Jordi Surrallés, Cristina Díaz de Heredia, Julián Sevilla, Paula Rio, Juan A. Bueren

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Figure 1

Comparative analysis of NKG2D-L levels in uncorrected and gene-corrected fibroblasts from patients with FA-A and HDs.

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Comparative analysis of NKG2D-L levels in uncorrected and gene-corrected...
(A) Primary fibroblasts from HDs (n = 6) and patients with FA-A (n = 8) were cultured at a similar confluence, and NKG2D-L levels were analyzed with a mixture of anti–NKG2D-L antibodies (anti-MICA, -MICB, and –ULBP1-6). Data show the ratio of the MFI of NKG2D-L staining with respect to basal fluorescence. (B) Fold increase of NKG2D-L levels in MMC-treated (+MMC) versus untreated (–MMC) fibroblasts from HDs (n = 7) and patients with FA-A (n = 8). Primary fibroblasts were maintained for 3 days in the absence or presence of MMC (33 nM and 100 nM). NKG2D-L MFI ratios of MMC-treated to nontreated cells are shown. (C) Levels of NKG2D-L (MFI values) in uncorrected and gene-corrected fibroblasts from 3 patients with FA-A. The fibroblasts were exposed to 0 nM, 33 nM, or 100 nM MMC. Corrected cells were generated by transduction with a RV carrying the FANCA gene (+FANCA), whereas uncorrected cells consisted of either untransduced cells (MOCK) or cells transduced with a RV encoding FANCG (+FANCG). Representative histograms of NKG2D-L levels in fibroblasts from patient FA-707 are also shown (lower panels). (D) Fold increase of NKG2D-L levels in formaldehyde-treated fibroblasts versus untreated fibroblasts corresponding to FA-competent cells (HD or corrected FA-A cells; FA-A+FANCA) or FA pathway–deficient cells (untransduced; FA-A or FANCC or FANCG-transduced FA-A cells; FA-A+FANCC/G). Data in A, B, and D represent the mean ± SEM. A 2-tailed, unpaired t test was used to compare mean values between HD and FA fibroblasts, either corrected or uncorrected.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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