期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 32, 页码 13224-13229出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1101398108
关键词
hematopoiesis; humanized mice; leukocyte homeostasis
资金
- Bill and Melinda Gates Foundation
- Wijnand M. Pon Foundation
- College de France
- Fondation pour la Recherche Medicale (FRM)
- Institut Pasteur
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Human Frontiers Science Program
- Dutch Cancer Society [NKI 2006-3530]
The homeostatic control mechanisms regulating human leukocyte numbers are poorly understood. Here, we assessed the role of phagocytes in this process using human immune system (HIS) BALB/c Rag2(-/-)IL-2R gamma c(-/-) mice in which human leukocytes are generated from transplanted hematopoietic progenitor cells. Interactions between signal regulatory protein alpha (SIRP alpha; expressed on phagocytes) and CD47 (expressed on hematopoietic cells) negatively regulate phagocyte activity of macrophages and other phagocytic cells. We previously showed that B cells develop and survive robustly in HIS mice, whereas T and natural killer (NK) cells survive poorly. Because human CD47 does not interact with BALB/c mouse SIRP alpha, we introduced functional CD47/SIRP alpha interactions in HIS mice by transducing mouse CD47 into human progenitor cells. Here, we show that this procedure resulted in a dramatic and selective improvement of progenitor cell engraftment and human T- and NK-cell homeostasis in HIS mouse peripheral lymphoid organs. The amount of engrafted human B cells also increased but much less than that of T and NK cells, and total plasma IgM and IgG concentrations increased 68- and 35-fold, respectively. Whereas T cells exhibit an activated/memory phenotype in the absence of functional CD47/SIRP alpha interactions, human T cells accumulated as CD4(+) or CD8(+) single-positive, naive, resting T cells in the presence of functional CD47/SIRP alpha interactions. Thus, in addition to signals mediated by T cell receptor (TCR)/MHC and/or IL/IL receptor interactions, sensing of cell surface CD47 expression by phagocyte SIRP alpha is a critical determinant of T- and NK-cell homeostasis under steady-state conditions in vivo.
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