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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-08, Vol.108 (32), p.13224-13229
• Main Authors: Legrand, Nicolas, Huntington, Nicholas D, Nagasawa, Maho, Bakker, Arjen Q, Schotte, Remko, Strick-Marchand, Hélène, de Geus, Sandra J, Pouw, Stephan M, Böhne, Martino, Voordouw, Arie, Weijer, Kees, Di Santo, James P, Spits, Hergen
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Differentiation - metabolism; B lymphocytes; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; Biological Sciences; CD4 antigen; CD47 Antigen - metabolism; CD8 antigen; Cell surface; Cells; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - metabolism; Gene expression; Genotype & phenotype; Hematopoietic Stem Cell Transplantation; hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Hemopoiesis; Homeostasis; Humans; Immune system; Immunoglobulin G; Immunoglobulin M; Interleukin Receptor Common gamma Subunit - metabolism; Killer Cells, Natural - cytology; Killer Cells, Natural - metabolism; Kinetics; Leukocytes; Lymphocytes B; Lymphocytes T; Lymphopoiesis; Macrophages; Major histocompatibility complex; memory; Memory cells; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Myeloid cells; Natural killer cells; Phagocytes; phenotype; Protein Binding; Proteins; Receptors, Immunologic - metabolism; Receptors, Interleukin-2 - deficiency; Receptors, Interleukin-2 - metabolism; regulatory proteins; signal regulatory proteins; Signal transduction; Social interaction; Spleen; Spleen - cytology; Spleen - immunology; Stem cells; Survival Analysis; T lymphocytes; T-cell receptor; T-Lymphocytes - cytology; T-Lymphocytes - metabolism; Thymus Gland - metabolism; Transplantation, Heterologous
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1101398108

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.