Functional CD47/signal regulatory protein alpha (SIRPα) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo
Functional CD47/signal regulatory protein alpha (SIRPα) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo
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DOI：
10.1073/pnas.1101398108
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发表时间：
2011-08-09
影响因子：
11.1
通讯作者：
Spits, Hergen
中科院分区：
文献类型：
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作者：
Legrand, Nicolas;Huntington, Nicholas D.;Spits, Hergen
调节人类白细胞数量的稳态控制机制知之甚少。在此，我们使用人类免疫系统（HIS）BALB/c Rag 2（-/-）IL-2 R γ c（-/-）小鼠评估吞噬细胞在此过程中的作用，其中人类白细胞由移植的造血祖细胞产生。信号调节蛋白α（SIRP α;在吞噬细胞上表达）和CD 47（在造血细胞上表达）之间的相互作用负调节巨噬细胞和其他吞噬细胞的吞噬细胞活性。我们先前表明，B细胞在HIS小鼠中发育和存活，而T和自然杀伤（NK）细胞存活较差。由于人CD 47不与BALB/c小鼠SIRP α相互作用，我们通过将小鼠CD 47转导入人祖细胞，在HIS小鼠中引入功能性CD 47/SIRP α相互作用。在这里，我们表明，这一程序导致了显着的和选择性的改善祖细胞植入和人类T-和NK细胞的稳态在HIS小鼠外周淋巴器官。移植的人B细胞的量也增加，但远低于T和NK细胞的量，总血浆IgM和IgG浓度分别增加68倍和35倍。尽管T细胞在不存在功能性CD 47/SIRP α相互作用的情况下表现出活化/记忆表型，但人T细胞在存在功能性CD 47/SIRP α相互作用的情况下积累为CD 4（+）或CD 8（+）单阳性、初始、静息T细胞。因此，除了由T细胞受体（TCR）/MHC和/或IL/IL受体相互作用介导的信号之外，吞噬细胞SIRP α对细胞表面CD 47表达的感测是体内稳态条件下T细胞和NK细胞稳态的关键决定因素。
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.