Legrand, N, Huntington, ND, Nagasawa, M, Bakker, AQ, Schotte, R, Strick-Marchand, H et al.. Functional CD47/signal regulatory protein alpha (SIRP(alpha)) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo. Proc Natl Acad Sci USA 108: 13224-13229

Department of Cell Biology and Histology, Academic Medical Center of the University of Amsterdam, Center for Immunology Amsterdam, 1105AZ Amsterdam, The Netherlands.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2011; 108(32):13224-9. DOI: 10.1073/pnas.1101398108
Source: PubMed


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-2Rγc(-/-) mice in which human leukocytes are generated from transplanted hematopoietic progenitor cells. Interactions between signal regulatory protein alpha (SIRPα; 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 SIRPα, we introduced functional CD47/SIRPα 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/SIRPα interactions, human T cells accumulated as CD4(+) or CD8(+) single-positive, naive, resting T cells in the presence of functional CD47/SIRPα 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 SIRPα is a critical determinant of T- and NK-cell homeostasis under steady-state conditions in vivo.

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    • "). Detailed genomic, transcriptomic , and functional analysis of candidate genes in the introgressed 129-derived region in B6.129-Prnp ZrchI/ZrchI mice supported a focus on the well-characterized inhibitor of phagocytosis Sirpa, whose polymorphisms alter this phenotype (Takenaka et al., 2007; Legrand et al., 2011; Strowig et al., 2011). Indeed, Sirpa 129 , rather than Prnp  , segregated with increased phagocytosis. "
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    Journal of Experimental Medicine 10/2013; 210(12). DOI:10.1084/jem.20131274 · 12.52 Impact Factor
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    • "In this scenario, HIV-1 resistant shRNA-expressing cells are likely to be positively selected, as the unprotected cells will be removed by the immune system upon HIV-1 infection, leading to a clinical benefit for the patient. Still, this hypothesis remains to be formally proven, and alternative therapeutic strategies can also be envisioned, e.g., using clinical-grade cell sorting of modified cells – as already performed in HIS mice47 – or in vivo delivery of T cell-targeted shRNA.13 It should be emphasized that human T-cell homeostasis is particularly sub-optimal in BRG-HIS mice.15,18,19 "
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    Molecular Therapy - Nucleic Acids 09/2013; 2(9):e120. DOI:10.1038/mtna.2013.48 · 4.51 Impact Factor
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    • "Other groups have also shown that functional species-specific CD47/SIRPα interaction is required for generating improved models of mouse/human chimeras: mouse CD47-expression in transplanted human hematopoietic cells is required for optimal human T- and natural killer-cell homeostasis in mice [24]. Furthermore, the introduction of mouse CD47 into primary human hepatocytes confers a positive selective advantage upon engraftment into the mouse liver in vivo [25]. "
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    PLoS ONE 03/2013; 8(3):e58359. DOI:10.1371/journal.pone.0058359 · 3.23 Impact Factor
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