Activation of Notch1 promotes development of human CD8 single positive T cells in humanized mice |
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Authors: | Yoichi Haji Makiko Suzuki Kunihiko Moriya Takanori So Katsuto Hozumi Masamichi Mizuma Michiaki Unno Naoto Ishii |
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Institution: | 1. Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;2. Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;3. Department of Immunology, Tokai University School of Medicine, Isehara 259-1193, Japan |
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Abstract: | Notch1 mutations are found in more than 50% of human T cell acute lymphoblastic leukemia (T-ALL) cells. However, the functions of Notch1 for human T cell development and leukemogenesis are not well understood. To examine the role of Notch1, human hematopoietic stem cells (HSCs), which had been transduced with a constitutively active form of Notch1 (ICN1), were transplanted into severely immunodeficient NOD/Shi-scid-IL2rγnull (NOG) mice. We found that the great majority of the ICN1-expressing hematopoietic cells in the bone marrow expressed surface markers for T cells, such as CD3, CD4, and CD8, and that this T cell development was independent of the thymus. Accordingly, phenotypically mature CD8+ single positive (SP) T cells were observed in the spleen. Furthermore, T-ALL developed in one NOG recipient mouse out of 26 that had been secondary transferred with the T cells developed in the first NOG mice. These results indicate that Notch1 signaling in HSCs promotes CD8+ SP T cell development, and that T cell leukemogenesis may require additional oncogenic factors other than Notch1 activation. |
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Keywords: | HSC hematopoietic stem cell DN CD4+ and CD8+ double-negative DP CD4+ and CD8+ double-positive ICN1 intracellular domain of Notch1 SP single positive T-ALL T cell acute lymphoblastic leukemia NOG NOD/Shi-scid-IL2rγnull mAb monoclonal antibody EGFP enhanced green fluorescent protein |
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