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The Journal of Immunology, 2000, 164: 9-12.
Copyright © 2000 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Signal-Regulatory Protein ß1 Is a DAP12-Associated Activating Receptor Expressed in Myeloid Cells1

Jes Dietrich2,*, Marina Cella*, Martina Seiffert{dagger}, Hans-Jörg Bühring{dagger} and Marco Colonna2,*

* Basel Institute for Immunology, Basel, Switzerland; and {dagger} University of Tübingen, Department of Internal Medicine II, Division of Hematology, Immunology and Oncology, Tübingen, Germany


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Signal-regulatory proteins (SIRPs) are cell-surface glycoproteins expressed on myeloid and neural cells that have been shown to recruit SH2 domain-containing protein phosphatase 1 (SHP-1) and SHP-2 and to regulate receptor tyrosine kinase-coupled signaling. One SIRP of unknown function, designated SIRPß1, contains a short cytoplasmic domain that lacks sequence motifs capable of recruiting SHP-1 and SHP-2. Using a SIRP-specific mAb, we show that SIRPß1 is expressed in monocytes and dendritic cells and associates with the signal transduction molecule DAP12. SIRPß1/DAP12 complex formation was required for efficient cell-surface expression of SIRPß1. Stimulation of this complex induced tyrosine phosphorylation, mitogen-activated protein kinase activation, and cellular activation. Thus, SIRPß1 is a new DAP12-associated receptor involved in the activation of myeloid cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Signal-regulatory proteins (SIRPs)3 comprise several transmembrane glycoproteins expressed in neurons and myeloid cells, including macrophages, monocytes, granulocytes, and dendritic cells (DCs) (1, 2, 3, 4). These molecules are also called src homology 2 domain-containing phosphatase substrate-1 (3), brain Ig-like molecules with a tyrosine-based activation motif (5), P84 (6), and macrophage fusion receptor (7). Structurally, SIRPs are characterized by three homologous extracellular Ig superfamily domains and by different transmembrane and cytoplasmic domains (1). One subset of SIRPs, called SIRP{alpha}, displays cytoplasmic domains containing immunoreceptor tyrosine-based inhibitory motifs, which recruit protein tyrosine phosphatase SHP-2 (SH2 domain-containing protein phosphatase 2) (1) and SHP-1 (2, 3). Accordingly, SIRP{alpha} was shown to inhibit receptor tyrosine kinase-coupled signaling pathways (1). However, SIRP{alpha}1 was also shown to potentiate early events in integrin signaling (8) and to positively regulate the mitogen-activated protein kinase (MAPK) signaling cascade in response to insulin when overexpressed in transfected cells (9). Thus, in certain circumstances SIRP{alpha}1 may mediate stimulation rather than inhibition. The ligand for SIRP{alpha} was recently found to be CD47, an integrin-associated protein with multiple functions in immunological and neuronal processes (10, 11). Consistent with this observation, SIRP{alpha}1 was shown to be phosphorylated in response to cell adhesion in macrophages as well as in nonhematopoietic cells (12, 13).

Another subset of SIRP receptors, called SIRPß, contains short cytoplasmic domains that lack cytoplasmic sequence motifs capable of recruiting SHP-2 and SHP-1. In addition, they contain a single basic lysine residue within the hydrophobic transmembrane domain (1). These characteristics are reminiscent of those of a group of NK cell receptors which includes the killer cell Ig-like receptors with short tails (KIR2DS), the CD94-NKG2C/E heterodimers, and Ly49D/H homodimers. These NK cell receptors activate cell-mediated cytotoxicity and cytokine release by associating with a separate 12-kDa protein, called DAP12, which contains a single cytoplasmic immunoreceptor tyrosine-based activating motif (14, 15, 16). To examine the possible association of SIRPß1 with DAP12, we generated a specific mAb and examined cellular distribution, biochemical composition, and signaling properties of SIRPß1.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Generation of mAb

BALB/c mice were immunized with human DCs. Myeloid cell-specific mAbs were selected by staining peripheral blood leukocytes and DCs. Anti-SIRPß1 mAb 148 was further selected by screening against SIRPß1-COS transfectants.

Cells and transfectants

Human monocytic (U937 and monomac-6), NK, and T (Jurkat) cell lines were grown in RPMI 1640 with 10% FCS. Human peripheral blood monocytes, DCs, polyclonal NK, and T cell lines were obtained and cultured as described (17). SIRPß1 and SIRP{alpha}1 cDNAs were cloned into pCDNA3 (Invitrogen, Carlsbad, CA) and transiently expressed in COS cells using Superfect (Quiagen, Hilden, Germany). SIRPß1 and DAP12 cDNAs were cotransfected in Jurkat cells by electroporation, and SIRPß1-DAP12 stable transfectants were selected in G418-containing medium. SIRPß1 expression on transfected cells was assessed by FACS analysis and immunoblot using mAb 148. Coexpression of DAP12 in double transfectants was determined by anti-DAP12 immunoblot on either whole cell lysates or SIRPß1 immunoprecipitates (see below).

Immunoprecipitation and immunoblotting

Pervanadate-treated (200 µM sodium orthovanadate and 200 µM H2O2 at 37°C for 10 min) monocytes, monomac-6 cells, and SIRPß1-DAP12-Jurkat cells were lysed in 1% Triton X-100, precleared with protein G beads (Amersham Pharmacia, Uppsala, Sweden) and normal mouse serum, and subjected to immunoprecipitation with mAb 148 as previously described (18). For whole cell lysate analysis, cells were lysed in Laemmli sample buffer. Immunoprecipitates and whole cell lysates were separated by standard SDS-PAGE, transferred to polyvinylidene difluoride membranes (Amersham Pharmacia), and immunoblotted with mAb 148 and/or rabbit anti-DAP12 antiserum (kindly provided by Dr. Kerry S. Campbell, Philadelphia, PA). In some experiments the precipitates were treated overnight with N-glycanase F (Boehringer Mannheim, Mannheim, Germany) according to the manufacture’s protocols.

Cell stimulations

Two million cells/ml were incubated at 37°C with mAb 148 or control IgG (Immunotech, Marseille, France) and F(ab')2 goat anti-mouse Ab (GAM) (Jackson Laboratories, West Grove, PA) as cross-linker. After stimulation, one cell aliquot was lysed and subjected to antiphosphotyrosine and anti-extracellular signal-regulated kinase (ERK) blotting using PY-20 (Transduction Laboratories, Lexington, KY) and either anti-phospho-ERK or ERK Abs (New England Biolabs, Beverly, MA). Alternatively, after 12 h of stimulation, another cell aliquot was analyzed for expression of CD69 by FACS analysis using a PE-conjugated anti-CD69 mAb (Immunotech).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
SIRPß1 is a ~50-kDa cell-surface glycoprotein expressed on monocytes and DCs

To obtain a SIRPß1-specific Ab we screened a panel of myeloid cell-specific mAbs against SIRPß1-COS transfectants. mAb 148 stained SIRPß1-COS transfectants as well as SIRP{alpha}1-COS transfectants compared with the staining of COS cells (Fig. 1GoA). SIRPß1/SIRP{alpha}1 cross-reactivity was expected because the extracellular regions of SIRPß1 and SIRP{alpha}1 are ~80% identical (1). In Western blotting, mAb 148 specifically detected a prominent protein of ~50 kDa in SIRPß1-COS cells and a ~90 kDa protein in SIRP{alpha}1-COS cells (Fig. 1GoB). Proteins with similar m.w. were found in monomac-6 cells (Fig. 1GoC).



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  		FIGURE 1. SIRPß1 is a 50-kDa glycoprotein expressed in myeloid cells. A, SIRPß1-COS and SIRP{alpha}1-COS cells (open profiles) were stained with mAb 148 and PE-conjugated GAM and analyzed by flow cytometry. Filled profiles represent COS cells. B and C, Whole cell lysates of COS, SIRPß1-COS, SIRP{alpha}1-COS (B), and monomac-6 (C) were analyzed by Western blot using mAb 148. D and E, SIRPß1/{alpha}1 precipitates from SIRPß1-COS (D) and monomac-6 (E) cells were left untreated (-) or treated (+) with N-glycanase F for 12 h and were analyzed by Western blot using mAb 148. Glycosylated SIRPß1 overlaps with the IgH of mAb 148. F, Cellular distribution of SIRPß1 by Western blot determined with mAb 148. Cells, molecular masses (in kDa), and position of SIRP{alpha}1 and SIRPß1 are indicated in the figure.

 
Following immunoprecipitation of SIRPß1 from SIRPß1-COS cells with mAb 148 and N-glycanase F treatment of the immunoprecipitate, SIRPß1 was seen as a ~40-kDa protein (Fig. 1GoD). A similar band was observed in monomac-6 cells, together with an additional band of ~65 kDa, which corresponds to the predicted m.w. of nonglycosylated SIRP{alpha}1 (Fig. 1GoE). Thus, mAb 148 recognizes SIRPß1 as well as SIRP{alpha}1. Using mAb 148 we next studied the cellular distribution of SIRPß1. SIRPß1 was detected in lysates from U937, monomac-6, and DCs, but were not found in peripheral NK/CD8 T cells, NK, or Jurkat cells (Fig. 1GoF). The presence in some cell lysates of more than one band in the 50-kDa region suggests that SIRPß1 may be present in more that one glycosylated form. SIRPß1 was always coexpressed with a more abundant ~90-kDa protein, which corresponds to SIRP{alpha}. Taken together, these results indicate that SIRPß1 is a 50-kDa cell-surface glycoprotein preferentially expressed in myeloid cells.

SIRPß1 associates with DAP12

DAP12 and other signaling proteins like TCR{zeta}, FcR{gamma}, and the recently identified DAP10/KAP10 (19, 20) have been shown to be tyrosine phosphorylated upon stimulation or after pervanadate treatment. Therefore, we tested whether SIRPß1 associated with a phosphorylated protein in myeloid cells. SIRPß1 precipitates from pervanadate-stimulated monocytes were analyzed by antiphosphotyrosine immunoblotting. SIRPß1 did associate with a phosphorylated protein with a molecular mass of ~26 kDa under nonreducing conditions, which decreased to ~14 kDa under reducing conditions (Fig. 2GoA). Subsequent analysis of SIRPß1 immunoprecipitates from unstimulated cells with an anti-DAP12 antiserum revealed that this molecule corresponds to DAP12 (Fig. 2GoB). Control immunoblotting experiments revealed no association of SIRPß1 with other myeloid adapter proteins, such as DAP10/KAP10 or FcR{gamma} (data not shown). Thus, in myeloid cells, SIRPß1 is constitutively associated with a DAP12 homodimer.



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  		FIGURE 2. SIRPß1 associates with the adaptor protein DAP12. A, Monocytes were treated with pervanadate, and SIRPß1 was precipitated with mAb 148 or control Ab (cIg). The precipitate was analyzed in Western blot under reducing or nonreducing conditions for tyrosine phosphorylated proteins. B, SIRPß1 was precipitated from untreated monomac-6 cells and analyzed under reducing conditions for DAP12 association. The molecular masses are given at the side in kDa. DAP12 and Ig light chain (IgL) are indicated in the figure.

 
SIRPß1/DAP12 complex triggers cell activation and ERK1/ERK2 phosphorylation

Because monocytes and DCs coexpress inhibitory and activating SIRP isotypes and mAb 148 recognizes both isotypes, it is difficult to investigate the function of SIRPß1 independently from that of SIRP{alpha}1 in primary cells. Therefore, to explore the possible stimulatory function of SIRPß1, we cotransfected SIRPß1 and DAP12 in Jurkat T cells, which do not express SIRP{alpha}1, SIRPß1, or DAP12 (Figs. 1GoF and 3). Expression of SIRPß1 in transfected cells was confirmed by immunoblot and surface staining (Fig. 3Go, A and B). Coexpression and association of DAP12 with SIRPß1 were monitored by anti-DAP12 immunoblotting on whole cell lysates and SIRPß1 immunoprecipitates (Fig. 3Go, C and D). Interestingly, cell surface expression of SIRPß1 was significantly lower in Jurkat cells transfected with SIRPß1 alone, indicating that DAP12 is required for efficient cell-surface expression of SIRPß1 (Fig. 3GoE).



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  		FIGURE 3. Association of SIRPß1 with the adaptor protein DAP12 in SIRPß1-DAP12-Jurkat cells allows efficient cell-surface expression of SIRPß1. A, Western blot analysis of lysates from SIRPß1-DAP12-Jurkat, Jurkat, and monomac-6 cells using mAb 148. B, Jurkat (filled profile) and SIRPß1-DAP12-Jurkat cells (open profile) were tested for cell-surface expression of SIRPß1 by flow cytometry with mAb 148. C, Western blot analysis of lysates from SIRPß1-DAP12-Jurkat, monomac-6, and Jurkat cells using a rabbit antiserum against DAP12. D, SIRPß1 precipitate from SIRPß1-DAP12-Jurkat or Jurkat cells was analyzed by Western blotting under reducing conditions for the presence of DAP12. E, Comparison of cell-surface expression of SIRPß1 in SIRPß1-DAP12 and SIRPß1 transfectants. The molecular masses are given at the side in kDa, and DAP12 and Ig light chain (IgL) are indicated in the figure.

 
We first examined whether SIRPß1 can trigger tyrosine phosphorylation. Aliquots of SIRPß1-DAP12-transfected cells were either left untreated, or stimulated for 2 or 5 min with mAb 148 and then with a cross-linking Ab and then lysed. Whole cell lysates were subsequently analyzed by antiphosphotyrosine immunoblotting. As shown in Fig. 4GoA, SIRPß1 stimulation led to a substantial increase in tyrosine phosphorylation of several proteins with apparent molecular masses of ~40, ~70, and ~100 kDa compared with the untreated cells. To examine whether the observed 40-kDa tyrosine-phosphorylated proteins corresponded to MAPK, immunoblotting analysis was performed using mAbs specific for activated forms of ERK1 and ERK2. As shown in Fig. 4GoB, Ab cross-linking of SIRPß1 did induce substantial phosphorylation of the ERK1 and ERK2. Finally, we tested whether stimulation of SIRPß1 also triggered expression of early cell surface activation markers in SIRPß1-DAP12-Jurkat cells. As shown in Fig. 4GoC, after overnight culture in the presence of anti-SIRPß1 and cross-linking Ab, CD69 expression was up-regulated ~2.5-fold compared with expression in untransfected cells. The signaling observed following SIRPß1 cross-linking was strictly dependent upon DAP12 expression because SIRPß1 single transfectants induced little or no tyrosine phosphorylation, ERK activation, or CD69 up-regulation. Because SIRPß1 expression is higher on the cell surface of SIRPß1-DAP12 cells than on SIRPß1 cells, it could be argued that cross-linking of SIRPß1 in double-transfected cells may lead to unspecific cross-linking of TCR, which is also known to up-regulate CD69. However, in control experiments, cross-linking of a highly expressed cell-surface molecule, such as MHC class I, did not lead to CD69 up-regulation (Fig. 4GoC).



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  		FIGURE 4. SIRPß1 is an activating receptor. A, Phosphotyrosine blot analysis of lysates from SIRPß1-DAP12-Jurkat cells or SIRPß1-Jurkat cells stimulated with mAb 148 and GAM as cross-linker for the indicated time periods. B, Cells were stimulated with mAb 148 and GAM for 5 min and the amount of activated ERK1 and ERK2 was examined by Western blot analysis using mAbs specific for activated ERKs (upper panels). Equal amounts of ERKs in each lane were confirmed by reblotting with an anti-ERK Ab (lower panels). C, SIRPß1-DAP12-Jurkat, SIRPß1-Jurkat, and Jurkat cells were incubated with mAb 148 and/or GAM. Additionally, Jurkat cells were incubated with anti-MHC class I mAb w6/32 and/or GAM. After 12 h incubation, cells were collected, stained with PE-conjugated anti-CD69 Ab, and analyzed by flow cytometry. The increase in CD69 surface expression was determined compared with the mean fluorescence intensity of untreated cells. The molecular masses, Ig heavy chain (IgH), cells, and mAbs are indicated in the figure.

 
Taken together, our results show that SIRPß1 is an activating myeloid receptor that forms a complex with a DAP12 homodimer. Association with DAP12 is required for efficient cell-surface expression of SIRPß1. Upon stimulation, SIRPß1/DAP12 complex induces tyrosine phosphorylation of a number of proteins as well as cellular activation. The observed signaling properties of SIRPß1/DAP12 are in agreement with previous results which demonstrate that NK cell receptor/DAP12 complexes induce tyrosine phosphorylation and MAPK activation in NK cells and CD69 up-regulation in KIR2DS2-DAP12-Jurkat cells (14, 15, 16, 18, 21, 22, 23). Interestingly, SIRPß1 was expressed in myeloid cells, but not in T cells or NK cells. This result, together with the recent discovery of a DAP12-associated C-type lectin called MDL-1 (24), which is also expressed in myeloid cells, indicates that myeloid cells, like NK cells, express a growing number of activating receptors that need to associate with DAP12 to transduce stimulatory signals. What could be the function of these receptors? Myeloid cell activation may lead to secretion of proinflammatory cytokines and chemokines. Particularly in DCs, activation may promote maturation, up-regulation of MHC, and costimulatory molecules, allowing DCs to prime T cells. We have also observed that myeloid cells express both inhibitory and activating SIRP isotypes. It will be important to determine whether these receptors mediate opposing functions or control separate signal transduction pathways in a coordinated manner.


   Acknowledgments
 
We thank Pasquale Vito and Raul Torres for critically reading the manuscript and Kerry S. Campbell for anti-DAP12 antiserum.


   Footnotes
 
1 This work was supported by the Basel Institute for Immunology, founded and supported by F. Hoffmann-La Roche Ltd., Basel, Switzerland. J.D. was recipient of a postdoctoral fellowship from the Danish Medical Research Counsel. H.-J.B. was supported by the Deutsche Forschungsgemeinschaft (SFB510, project A1) and by a grant from the Jose Carreras Foundation (Carreras/Bü-1). Back

2 Address correspondence and reprint requests to Drs. Jes Dietrich or Marco Colonna, Basel Institute for Immunology, Grenzacherstrasse 487, CH-4005, Basel, Switzerland. E-mail addresses: Back

3 Abbreviations: SIRP, signal regulatory proteins; ERK, extracellular-signal regulated kinase; MAPK, mitogen activated protein kinase; GAM, goat anti-mouse Ab; SHP-1 and -2, SH2 domain-containing protein phosphatase 1 and 2; DC, dendritic cell. Back

Received for publication September 28, 1999. Accepted for publication November 2, 1999.


   References
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 Results and Discussion
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S. Nataf, A. Anginot, C. Vuaillat, L. Malaval, N. Fodil, E. Chereul, J.-B. Langlois, C. Dumontel, G. Cavillon, C. Confavreux, et al.
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G. W. Henkel, S. R. McKercher, and R. A. Maki
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A Dap12-Mediated Pathway Regulates Expression of Cc Chemokine Receptor 7 and Maturation of Human Dendritic Cells
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J. Dietrich, M. Cella, and M. Colonna
Ig-Like Transcript 2 (ILT2)/Leukocyte Ig-Like Receptor 1 (LIR1) Inhibits TCR Signaling and Actin Cytoskeleton Reorganization
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Cutting Edge: Inflammatory Responses Can Be Triggered by TREM-1, a Novel Receptor Expressed on Neutrophils and Monocytes
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