| First Author | Visconte V | Year | 2010 |
| Journal | Haematologica | Volume | 95 |
| Issue | 2 | Pages | 214-23 |
| PubMed ID | 19679885 | Mgi Jnum | J:162065 |
| Mgi Id | MGI:4462352 | Doi | 10.3324/haematol.2009.011650 |
| Citation | Visconte V, et al. (2010) Phenotypic and functional characterization of a mouse model of targeted Pig-a deletion in hematopoietic cells. Haematologica 95(2):214-23 |
| abstractText | BACKGROUND: Somatic mutation in the X-linked phosphatidylinositol glycan class A gene (PIG-A) causes glycosyl phosphatidylinositol anchor deficiency in human patients with paroxysmal nocturnal hemoglobinuria. DESIGN AND METHODS: We produced an animal model of paroxysmal nocturnal hemoglobinuria by conditional Pig-a gene inactivation (Pig-a(-/-)) in hematopoietic cells; mice carrying two lox sites flanking exon 6 of the Pig-a gene were bred with mice carrying the transgene Cre-recombinase under the human c-fes promoter. We characterized the phenotypic and functional properties of glycosyl phosphatidylinositol-deficient and glycosyl phosphatidylinositol-normal hematopoietic cells from these Pig-a(-/-) mice using gene expression microarray, flow cytometry, bone marrow transplantation, spectratyping, and immunoblotting. RESULTS: In comparison to glycosyl phosphatidylinositol-normal bone marrow cells, glycosyl phosphatidylinositol-deficient bone marrow cells from the same Pig-a(-/-) animals showed up-regulation of the expression of immune function genes and contained a significantly higher proportion of CD8 T cells. Both characteristics were maintained when glycosyl phosphatidylinositol-deficient cells were transplanted into lethally-irradiated recipients. Glycosyl phosphatidylinositol-deficient T cells were inactive, showed pronounced Vbeta5.1/5.2 skewing, had fewer gamma-interferon-producing cells after lectin stimulation, and contained fewer CD4(+)CD25(+)FoxP3(+) regulatory T cells. However, the levels of T-cell receptor signaling proteins from glycosyl phosphatidylinositol-deficient cells were normal relative to glycosyl phosphatidylinositol-normal cells from wild type animals, and cells were capable of inducing target cell apoptosis in vitro. CONCLUSIONS: Deletion of the Pig-a gene in hematopoietic cells does not cause frank marrow failure but leads to the appearance of clonally-restricted, inactive yet functionally competent CD8 T cells. |
