Using mice deficient in T, B, and NK cells, Dai et al. determined that the ability of myeloid cells to sense and respond to allogeneic grafts is dependent on the differential binding affinity between CD47 on host monocytes and polymorphisms in the extracellular domains of host or donor SIRPα. Dai et al. propose that non-self SIRPα alleles cause innate immune activation by disturbing the balance between activating and inhibitory signals.
Mice devoid of T, B, and natural killer (NK) cells distinguish between self and allogeneic nonself despite the absence of an adaptive immune system. When challenged with an allograft, they mount an innate response characterized by accumulation of mature, monocyte-derived dendritic cells (DCs) that produce interleukin-12 and present antigen to T cells. However, the molecular mechanisms by which the innate immune system detects allogeneic nonself to generate these DCs are not known. To address this question, we studied the innate response of Rag2-/- gammac-/- mice, which lack T, B, and NK cells, to grafts from allogeneic donors. By positional cloning, we identified that donor polymorphism in the gene encoding signal regulatory protein alpha (SIRPalpha) is a key modulator of the recipient's innate allorecognition response. Donors that differed from the recipient in one or both Sirpa alleles elicited an innate alloresponse. The response was mediated by binding of donor SIRPalpha to recipient CD47 and was modulated by the strength of the SIRPalpha-CD47 interaction. Therefore, sensing SIRPalpha polymorphism by CD47 provides a molecular mechanism by which the innate immune system distinguishes between self and allogeneic nonself independently of T, B, and NK cells.
Author Info: (1) Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. (2) Thomas E. Starzl Transplantation
Author Info: (1) Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. (2) Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. (3) Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. (4) Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. (5) Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G1X8, Canada. (6) Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. (7) Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. (8) Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. (9) Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Kobe 650-0017, Japan. (10) Heart, Lung, Blood, and Vascular Medicine Institute and Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. (11) Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G1X8, Canada. (12) Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G1X8, Canada. jayne.danska@sickkids.ca lakkisf@upmc.edu. Departments of Immunology and Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada. (13) Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. jayne.danska@sickkids.ca lakkisf@upmc.edu. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
