Functional CD47/signal regulatory protein alpha (SIRPα) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo

Abstract

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.hematopoiesis | humanized mice | leukocyte homeostasis

Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment

“…[31][32][33] A recent study also showed that transgenic expression of mouse CD47 into CD34 ϩ CD38 Ϫ human fetal liver cells significantly enhanced the human cell engraftment into BALB-RG mice. 34 Based on these data, the binding of NOD-SIRPA with human CD47 might produce signals for mouse macrophages not to engulf human HSCs, which presumably makes the strain permissive for human HSC engraftment. 24 The most important question was whether the NOD-specific highly efficient human cell engraftment in vivo could be explained solely by the NOD-Sirpa polymorphism.…”

Viral infections in mice with reconstituted human immune system components

“…Indeed transgenic or congenic expression of either the human or the NOD SIRP [10,11], or mouse CD47 gene transfer into reconstituting human hematopoietic cells GM-CSF and TPO [13]. These MISTRG mice developed myeloid and NK cells more efficiently than NSG mice, but still a significant variation in human immune system component reconstitution could be observed.…”

“…In contrast, BRG mice are usually less well reconstituted with human immune system components, often reaching only 10% of human hematopoietic cells in the peripheral blood after 3 months [10,11]. Xenoreactivity of the mouse myeloid compartment against the engrafting human cells was identified as the limiting factor.…”

Human allograft rejection in humanized mice: a historical perspective

“…38 The second study showed that retrogenic expression of murine CD47 in human HSC prior to transplantation significantly improved human immune system development. 37 Overall, these studies highlight the importance of strain selection in the efficient generation of humanized mice.…”

“…Two recent studies using distinct approaches have demonstrated that the SIRPa-CD47 interactions are critically important for the engraftment of human HSC and immune cell development in IL2rc null mice. 37,38 It was first shown that transgenic expression of human SIRPa by mice on a mixed (1293BALB/c) strain background significantly improved the engraftment of human HSC. 38 The second study showed that retrogenic expression of murine CD47 in human HSC prior to transplantation significantly improved human immune system development.…”