title: Functional CD47/signal regulatory protein alpha (SIRP(alpha)) 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.
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center of the University of Amsterdam, Center for Immunology Amsterdam, 1105AZ Amsterdam, The Netherlands. n.legrand@amc.uva.nl
authors.forename: Nicolas
authors.initials: N
authors.lastname: Legrand
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Huntington
authors.forename: Maho
authors.initials: M
authors.lastname: Nagasawa
authors.forename: Arjen Q
authors.initials: AQ
authors.lastname: Bakker
authors.forename: Remko
authors.initials: R
authors.lastname: Schotte
authors.forename: Hélène
authors.initials: H
authors.lastname: Strick-Marchand
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: de Geus
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Pouw
authors.forename: Martino
authors.initials: M
authors.lastname: Böhne
authors.forename: Arie
authors.initials: A
authors.lastname: Voordouw
authors.forename: Kees
authors.initials: K
authors.lastname: Weijer
authors.forename: James P
authors.initials: JP
authors.lastname: Di Santo
authors.forename: Hergen
authors.initials: H
authors.lastname: Spits
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D051928:CD47 Antigen / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000378:metabolism*; D007700:Kinetics; D038041:Lymphopoiesis; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000172:deficiency / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000943:Antigens, Differentiation; D051928:CD47 Antigen; D004268:DNA-Binding Proteins; D053631:Interleukin Receptor Common gamma Subunit; C499308:Rag2 protein, mouse; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; C501920:SIRPA protein, human