Signal-regulatory protein α (SIRPα) but not SIRPβ is involved in T-cell activation, binds to CD47 with high affinity, and is expressed on immature CD34+CD38- hematopoietic cells

Martina Seiffert, Peter Brossart, Charles Cant, Marina Cella, Marco Colonna, Wolfram Brugger, Lothar Kanz, Axel Ullrich, Hans Jörg Bühring

Research output: Contribution to journalArticle

132 Scopus citations

Abstract

Signal-regulatory proteins (SIRPs) represent a new family of inhibitory/activating receptor pairs. They consist of 3 highly homologous immunoglobulin (Ig)-Iike domains in their extracellular regions, but differ in their cytoplasmic regions by the presence (SlRPα) or absence (SlRPβ) of immunoreceptor tyrosine-based inhibitory motifs (ITIMs). To analyze the differential expression on hematopoietic cells, function and ligand binding capacity of SIRPα and SIRPβ molecules, soluble fusion proteins consisting of the extracellular domains of SIRPα1, SIRPα2, and SIRPβ1, as well as SIRPα/β-specific and SIRPβ-specific monoclonal antibodies (MoAbs) were generated. In contrast to SIRPα1 and SIRPα2, no adhesion of SIRPβ1 to CD47 could be detected by cell attachment assays and flow cytometry. Using deletion constructs of SIRPα1, the epitope responsible for SIRPα1 binding to CD47 could be confined to the N-terminal Ig-like loop. Flow cytometry analysis with SIRPα/β- and SIRPβ-specific MoAbs revealed that SIRPα but not SIRPα is expressed on CD34+CD38- hematopoietic cells. In addition, a strong SIRPα expression was also observed on primary myeloid dendritic cells (DCs) from peripheral blood as well as on in vitro generated DCs. Analysis of the T-cell stimulatory capacity of in vitro generated DCs in the presence of soluble SIRPα1 fusion proteins as well as SIRPα/β-specific and CD47-specific MoAbs revealed a significant reduction of T-cell proliferation in mixed lymphocyte reaction and inhibition of induction of primary T-cell responses under these conditions. In contrast, soluble SIRPα or SIRPβ-specific antibodies had no effect. The data suggest that the interaction of SIRPα with CD47 plays an important role during T-cell activation and induction of antigen-specific cytotoxic T-lymphocyte responses by DCs.

Original languageEnglish
Pages (from-to)2741-2749
Number of pages9
JournalBlood
Volume97
Issue number9
DOIs
StatePublished - May 1 2001
Externally publishedYes

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