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Immunoglobulin super-family inhibitory receptors: from natural killer cells to antigen-presenting cells
NK CELL FUNCTIONS AND RECEPTORS
Rouvier, E., Luciani, M.-F. & Golstein, P. (1993), Fas involvement in Ca 2+ -independent T cell-mediated cytotoxicity. J. Exp. Med., 177, 195-200. Smith, C.A., Williams, G.T., Kingston, R., Jenkinson, E.J. & Owen, J.J.T. (1989), Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T ceils in thymic cultures. Nature (Lond.), 337, 181-184. Suda, T., Okazaki, T., Naito, Y., Yokota, T., Arai, N., Ozaki, S., Nakao, K. & Nagata, S. (1995), Expression of the Fas ligand in cells of T cell lineage. J. Imrnunol., 154, 3806-3813. Tanaka, M., Suda, T., Haze, K., Nakamura, N., Sato, K., Kimura, F., Motoyoshi, K., Mizuli, M., Tagawa, S., Ohga, S., Hatake, K., Drummond, A.H. & Nagata, S. (1996), Fas ligand in human serum. Nature Med., 2, 317-322. Trenn, G., Takayama, H. & Sitkovsky, M.V. (1987), Exocytosis of cytolytic granules may not be required for target cell lysis by cytotoxic T-lymphocytes. Nature (Lond.) 330, 72-74.
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Tsutsui, H., Nakanishi, K., Matsui, K., Higashino, K., O k a m u r a , H., M i y a z a w a , Y. & Kaneda, K. (1996), IFN-7-inducing factor up-regulates Fas ligand-mediated cytotoxic acitvity of murine natural killer cell clones. J. lmmunol., 1.'57, 39673973. Walsh, C.M., Matloubian, M., Liu, C.-C., Ueda, R., Kurahara, C.G., Christensen, J.L., Huang, M.T.F., Young, J.D-E., Ahmed, R. & Clark, W.R. (1994), Immune function in mice lacking the perforin gene. Proc. Natl. Acad. Sci. USA, 91, 1085410858. Wiley, S.R., Schooley, K., Smolak, P.J., Din, W.S., Huang, C.P., Nicholl, J.K., Sutherland, G.R., Smith, T.D., Ranch, C., Smith, C.A. et al. (1996), Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity, 3, 673-682. Young, J.D. & Cohn, Z.A. (1986), Cell-mediated killing: a common mechanism. Cell, 46, 641642.
Immunoglobulin superfamily inhibitory receptors: from natural killer cells to antigen-presenting cells M. C o l o n n a Basel Institute f o r Immunology, Basel CH-4005, Switzerland
It has been extensively shown that inhibitory receptors regulate cell activation in B cells, natural killer (NK) cells, subsets of T cells and mast cells (Amigorena et al., 1992; Muta et a/.,1994; Daeron et al., 1995; D o o d y et al., 1995; Y o k o y a m a and Seaman, 1993; Lanier and Phillips, 1996; Lazetic et al., 1996; Katz et al., 1996; Wang etal., 1997; Rojo et al., 1997). In particular, human N K cells express c l o n a l l y d i s t r i b u t e d i n h i b i t o r y r e c e p t o r s of the immunoglobulin superfamily (Ig-SF) specific for HLA-A, -B and -C molecules (Moretta et al., 1993 ; Litwin et al., 1993; Colonna and Samaridis, 1995; W a g t m a n n et al., 1995 ; D ' A n d r e a et air, 1995 ; Dohring et al., 1996; Pende et al., 1996). These r e c e p t o r s , called killer cell i n h i b i t o r y r e c e p t o r s (KIRs), block NK-cell-mediated cytotoxicity upon
Received April 21, 1997.
binding to HLA class I ligands. Inhibition is mediated by cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) (Thomas, 1995), which consist of two tyrosine-x-x-leucine (Y-x-x-L) pairs separated by 26 amino acids. Engagement of killer cell inhibitory receptors (KIRs) with clas,; I molecules induces tyrosine p h o s p h o r y l a t i o n ,of either tyrosine residue, and subsequent recruitment of the protein tyrosine phosphatase SHP-1 (Burshtyn et al., 1996; Olcese et al., 1996; Campbell et al., 1996; Fry et al., 1996; Binstadt et al., 1996). Some N K cell receptors lack the I T I M s due to a premature truncation o f the c y t o p l a s m i c tail and t h e r e f o r e do not mediate NK-cell inhibition. On the contrary, this group of receptors has a stimulatory function (Moretta et al., 1995 ; Biassoni et al., 1996).
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69th F O R U M I N I M M U N O L O G Y
W e h a v e n o w e x t e n d e d the n o t i o n o f I g - S F inhibitory receptors to myeloid antigen presenting cells (APCs), by identifying a new molecule, called Ig-like transcript 3 (ILT3) that negatiw:ly regulates APC functional responses triggered via stimulatory receptors (Colonna, unpublished). ILT3 is selectively expressed by dendritic cells (DCs), monocytes and macrophages. It consists of an extracellular region of 2 I g - S F domains and of a c y t o p l a s m i c region with 3 putative ITIMs, which are similar to those found in KIRs, thereby suggesting an inhibitory function of ILT3. Using anti-lLT3 mAbs, we have shown that ILT3 is a - 5 5 - 6 0 - k D a monomer, which is not N-glycosylated, but is constitutively phosphorylated. Coligation of ILT3 to stimulatory receptors expressed by APCs results in extinction of the increased [Ca2+] i triggered by these receptors. We have also tested whether ILT3 is used by APCs for antigen uptake. ILT3 is efficiently internalized and, furthermore, it delivers its ligand to an intracellular compartment, where it is processed and presented on M H C class II molecules. Thus, ILT3 is a novel inhibitory receptor with a dual function: it can negatively regulate activation of APCs and it can function for antigen capture and presentation.
The ligand of I L T 3 is still unknown. ILT3 is closely related to Fc receptors such as the human F c ~ R (Maliszewski et al., 1990), suggesting that ILT3 may be a new Fc receptor. However, we did not detect any significant binding of human monomeric and heat-aggregated IgM, IgG, IgA and IgE to ILT3 transfectants. ILT3 also shows h o m o l o g y to KIRs, and thus, it may be a receptor for MHC class I molecules. We have investigated this possibility by analysing binding of soluble I L T 3 - H u l g G 1 fusion protein to M H C class I transfectants in the class Ideficient mutants 721.221. However, no significant binding could be detected by FACS analysis under the same experimental conditions in which KIRHulgG fusion proteins bind to M H C ,class I molecules. We are investigating the possibility that ILT3 is a receptor for cell surface molecules related to MHC class I molecules, such as non-classical class I molecules [CD1 (Porcelli, 1995), MR1 (Hashimoto et al., 1995), MIC ( B a h r a m et al., 1994)] or for serum factors such as complement components.
It is noteworthy that ILT3 is expressed on DCs. These are a unique type of leukocytes whose primary function is to capture antigens, process them and present them to T cells (Steinman, 1991). While the uptake and the processing of antigen is a major function of DCs, yet only a few mechanisms and receptors specialized for antigen capture and presentation h a v e b e e n found to be e x p r e s s e d on D C s (Jiang et al., 1995; Sallusto et al., 1995; Bieber et al., 1992). Our data indicate that ILT3 is a unique receptor expressed in DCs, able to target the ligand into processing and peptide-loading compartments.
We thank S. Bahrain and M. Celia for critical reading of the manuscript. The Basel Institute for Immunology was founded and is supported by F. Hoffmann-La Roche Ltd., CH 4002 Basel, Switzerland.
Another interesting feature of ILT3 is the presence of alternatively spliced forms in different cell t y p e s . T h i s p h e n o m e n o n has b e e n p r e v i o u s l y observed for the FcyRIIB, which is expressed in B lymphocytes and in myeloid cells in two different isoforms, called FcyRIIB 1 and FcyRIIB2, respectively (Amigorena et al., 1992; Muta et al., 1994). These isoforms are generated by alternative splicing of sequences encoded by the first intracytoplasmic exon of the FcyRIIB gene and differ by a 19-amino acids insertion in human FcyRIIB 1 (47 amino acids in mouse FcyRIIB 1). This insertion does not modify the inhibitory function of FcyRIIB. However, it prevents both FcyRII-mediated endocytosis and FcyRII-mediated antigen presentation (Amigorena et at., 1992; Muta et al., 1994). Thus, only myeloid cells are c a p a b l e of F c y R I I B r e c e p t o r - m e d i a t e d endocytosis. Similarly, ILT3 alternatively spliced isoforms generated in different tissues m a y have different antigen p r e s e n t a t i o n and/or signalling capacities.
Acknowledgements
References Amigorena, S., Bonnerot, C., Drake, J.R., Choquet, D., Hunziker, W., Guillet, J.G., Webster.. P., Sautes, C., Mellman, I. & Fridman, W.H. (1992.), Cytoplasmic domain heterogeneity and functions e f IgG Fc receptors in B lymphocytes. Science, 256, 1808-1812. Bahrain, S., Bresnahan, M., Geraghty, D.E. & Spies, T. (1994), A second lineage of mammalian major histocompatibility complex class I genes. Proc. Natl. Acad. Sci. USA, 91, 6259-6263. Biassoni, R., Cantoni, C., Falco, M., Verdiani, S., Bottino, C., Vitale, M., Conte, R., Poggi, A., Moretta, A. & Moretta, L. (1996), The human leukocyte antigen (HLA)-C-specific "activatory" or "inhibitory" natural killer cell receptors display highly homologous extracellular domains but differ in their transmembrane and intracytoplasmic portions. J. Exp. Med., 183, 645-650. Bieber, T., de la Salle, H., Wollenberg, A., Hakimi, J., Chizzonite, R., Ring, J., Hanau, D. & de la Salle, C. (1992), Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (Fc epsilon RI). J. Exp. Med., 175, 1285-1290, Binstadt, B.A., Brumbaugh, K.M., Dick:, C.J., Scharenberg, A.M., Williams, B.L., Colorma, M., Lanier, L.L., Kinet, J-P., Abraham, R.T. & Leibson, P.J. (1996), Sequential involvement of Lck and SHP-1 with MHC-recognizing receptors on NK Ceils inhib-
N K CELL F U N C T I O N S A N D R E C E P T O R S its FcR-Initiated tyrosine kinase activation. Immunity, 5, 629-638. Burshtyn, D.N., Scharenberg, A.M., Wagtrnann, N., Rajagopalan, S., Berrada, K., Yi, T., Kinet, J.P. & Long, E.O. (1996), Recruitment of tyrosine phosphatase HCP by the killer cell inhibitor receptor. Immunity, 4, 77-85. Campbell, K.S., Dessing, M., Lopez Botet, M., Celia, M. & Colonna, M. (1996), Tyrosine phosphorylation of a human killer inhibitory receptor recruits protein tyrosine phosphatase 1C. J. Exp. Med., 184, 93-100. Colonna, M. & Samaridis, J. (1995), Cloning of immunoglobulin-superfamily members associated with HLAC and HLA-B recognition by human natural killer cells. Science, 268, 405-408. D'Andrea, A., Chang, C., Franz Bacon, K., McClanahan, T., Phillips, J.H. & Lanier, L.L. (1995), Molecular cloning of NKB 1. A natural killer cell receptor for HLA-B allotypes. J. ImmunoL, 155, 2306-2310. Dacron, M., Latour, S., Malbec, O., Espinosa, E., Pina, P., Pasmans, S. & Fridman, W.H. (1995), The same tyrosine-based inhibition motif, in the intracytoplasmic domain of Fc gamma RIIB, regulates negatively BCR-, TCR-, and FcR-dependent cell activation. Immunity, 3, 635-646. Dohring, C., Scheidegger, D., Samaridis, J., Celia, M. & Colonna, M. (1996), A human killer inhibitory receptor specific for HLA-A..L lmmunol., 156, 3098-3101. Doody, G.M., Justement, L.B., Delibrias, C.C., Matthews, R.J., Lin, J., Thomas, M.L. & Fearon, D.T. (1995), A role in B cell activation for CD22 and the protein tyrosine phosphatase SHP. Science, 269, 242-244. Fry, A.M., Lanier, L.L. & Weiss, A. (1996), Phosphotyrosines in the killer cell inhibitory receptor motif of NKB 1 are required for negative signaling and for association with protein tyrosine phosphatase 1C. J. Exp. Med., 184, 295-300. Hashimoto, K., Hirai, M. & Kurosawa, Y. (1995), A gene outside the human MHC related to classical HLA class I genes. Science, 269, 693-695. Jiang, W., Swiggard, W.J., Heufler, C., Peng, M., Mirza, A., Steinman, R.M. & Nussenzweig, M.C. (1995), The receptor DEC-205 expressed by dendritic cells and thymic epithelial cells is involved in antigen processing. Nature (Lond.), 375, 151-155. Katz, H.R., Vivier, E., Castells, M.C., McCormick, M.J., Chambers, J.M. & Austen, F.K. (1996), Mouse mast cell gp49B1 contains two immunoreceptor tyrosinebased inhibition motifs and suppresses mast cell activation when coligated with the high-affinity Fc receptor for IgE. Proc. Natl. Acad. Sci., USA, 93, 10809-10814. Lanier, L.L. & Phillips, J.H. (1996), Inhibitory MHC class I receptor on NK cells and T cells. Immunol. Today, 17, 86-91. Lazetic, S., Chang, C., Houchins, J.P., Lanier, L.L. & Phillips, J.H. (1996), Human natural killer cell receptors involved in MHC class I recognition are disulfide linked heterodimers of CD94 and NKG2 subunits. J. Immunol., 157, 4741-4745. Litwin, V., Gumperz, J., Parham, P., Phillips, J.H. & Lanier, L.L. (1993), NKB1, a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules. J. Exp. Med., 178, 1321-1325. Maliszewski, C.R., March, C.J., Schoenborn, M.A., Gimpel, S. & Shen, L. (1990), Expression cloning of a
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human Fc receptor for IgA. J. Exp. Med., 172, 1665-1672. Moretta, A., Vitale, M., Bottino, C., Orengo, A.M., Morelli, L., Augugliaro, R., Barbaresi, M., Ciccone, E. & Moretta, L. (1993), P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities. J. Exp. Med., 178, 59"7-604. Moretta, A., Sivori, S., Vitale, M., Pende, D., Morel/i, L., Augugliaro, R., Bottino, C. & Moretta, L (1995), Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells. J. Exp. Med., 182, 875-884. Muta, T., Kurosaki, T., Misulovin, Z., Sanchez, lvl., Nussenzweig, M.C. & Ravetch, J.V. (1994), A 13-aminoacid motif in the cytoplasmic domain of Fc gamma RIIB modulates B-cell receptor signalling. Nature (Lond.), 368, 70-73. Olcese, L., Lang, P., Vely, F., Cambiaggi, A., Marguet, D., Blery, M., Hippen, K.L., Biassoni, R., Moretta, A., Moretta, L., Cambier, J.C. & Vivier, E. (1996), Human and mouse killer-cell inhibitory receptors recruit PTP1C and PTP1D protein tyrosine p,hosphatases. J. Immunol., 156, 4531-4534. Pende, D., Biassoni, R., Cantoni, C., Verdiani, S., Falco, M., di Donato, C., Accame, L., Bottino, C., Moretta, A. & Moretta, L. (1996), The natural killer cell receptor specific for HLA-A allotypes, a now;l member of the p58/p70 family of inhibitory receptors that is characterized by three immunoglobulin-like domains and is expressed as a 140-kD disulphidelinked dimer. J. Exp. Med., 184, 505-518. Porcelli, S.A. (1995), The CD1 family: a third lineage of antigen-presenting molecules. Adv. lmmunol., 59, 1-98. Rojo, S., Burshtyn, D.N., Long, E.O. & Wagtmann, N. (1997), Type I transmembrane receptor with inhibitory function in mouse mast cells and NK cells. J. Immunol., 158, 9-12. Sallusto, F., Celia, M., Danieli, C. & Lanzavecchia, A. (1995), Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class lI compartment: downregulation by cytokines and bacterial products. J. Exp. Med., 182, 389-400. Steinman, R.M. (1991), The dendritic cell system and its role in immunogenicity. Annu. Rev. lmmunol., 9, 271-296. Thomas, M.L. (1995), Of ITAMs and ITIMs: turning on and off the B cell antigen receptor. J. Exp. MetL, 181, 1953-1956. Wagtmann, N., Biassoni, R., Cantoni, C., Verdiani, S., Malnati, M.S., Vitaie, M., Bottino, C., Moretta, L., Moretta, A. & Long, E.O. (1995), Molecular clones of the p58 NK cell receptor reveal immunoglobulinrelated molecules with diversity in both the extraand intracellular domains. Immunity, 2, 439-449. Wang, L.L., Mehta, I.K., LeBlanc, P.A. & Yokoyama, W.M. (1997), Mouse natural killer cells express gp49B1, a structural homologue of human killer inhibitory receptors. J. lmmunoL, 158, 13-17. Yokoyama, W.M. & Seaman, W.E. (1993), The Ly-49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex. Annu. Rev. Immunol., 11,613-635.
Rouvier, E., Luciani, M.-F. & Golstein, P. (1993), Fas involvement in Ca 2+ -independent T cell-mediated cytotoxicity. J. Exp. Med., 177, 195-200. Smith, C.A., Williams, G.T., Kingston, R., Jenkinson, E.J. & Owen, J.J.T. (1989), Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T ceils in thymic cultures. Nature (Lond.), 337, 181-184. Suda, T., Okazaki, T., Naito, Y., Yokota, T., Arai, N., Ozaki, S., Nakao, K. & Nagata, S. (1995), Expression of the Fas ligand in cells of T cell lineage. J. Imrnunol., 154, 3806-3813. Tanaka, M., Suda, T., Haze, K., Nakamura, N., Sato, K., Kimura, F., Motoyoshi, K., Mizuli, M., Tagawa, S., Ohga, S., Hatake, K., Drummond, A.H. & Nagata, S. (1996), Fas ligand in human serum. Nature Med., 2, 317-322. Trenn, G., Takayama, H. & Sitkovsky, M.V. (1987), Exocytosis of cytolytic granules may not be required for target cell lysis by cytotoxic T-lymphocytes. Nature (Lond.) 330, 72-74.
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Tsutsui, H., Nakanishi, K., Matsui, K., Higashino, K., O k a m u r a , H., M i y a z a w a , Y. & Kaneda, K. (1996), IFN-7-inducing factor up-regulates Fas ligand-mediated cytotoxic acitvity of murine natural killer cell clones. J. lmmunol., 1.'57, 39673973. Walsh, C.M., Matloubian, M., Liu, C.-C., Ueda, R., Kurahara, C.G., Christensen, J.L., Huang, M.T.F., Young, J.D-E., Ahmed, R. & Clark, W.R. (1994), Immune function in mice lacking the perforin gene. Proc. Natl. Acad. Sci. USA, 91, 1085410858. Wiley, S.R., Schooley, K., Smolak, P.J., Din, W.S., Huang, C.P., Nicholl, J.K., Sutherland, G.R., Smith, T.D., Ranch, C., Smith, C.A. et al. (1996), Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity, 3, 673-682. Young, J.D. & Cohn, Z.A. (1986), Cell-mediated killing: a common mechanism. Cell, 46, 641642.
Immunoglobulin superfamily inhibitory receptors: from natural killer cells to antigen-presenting cells M. C o l o n n a Basel Institute f o r Immunology, Basel CH-4005, Switzerland
It has been extensively shown that inhibitory receptors regulate cell activation in B cells, natural killer (NK) cells, subsets of T cells and mast cells (Amigorena et al., 1992; Muta et a/.,1994; Daeron et al., 1995; D o o d y et al., 1995; Y o k o y a m a and Seaman, 1993; Lanier and Phillips, 1996; Lazetic et al., 1996; Katz et al., 1996; Wang etal., 1997; Rojo et al., 1997). In particular, human N K cells express c l o n a l l y d i s t r i b u t e d i n h i b i t o r y r e c e p t o r s of the immunoglobulin superfamily (Ig-SF) specific for HLA-A, -B and -C molecules (Moretta et al., 1993 ; Litwin et al., 1993; Colonna and Samaridis, 1995; W a g t m a n n et al., 1995 ; D ' A n d r e a et air, 1995 ; Dohring et al., 1996; Pende et al., 1996). These r e c e p t o r s , called killer cell i n h i b i t o r y r e c e p t o r s (KIRs), block NK-cell-mediated cytotoxicity upon
Received April 21, 1997.
binding to HLA class I ligands. Inhibition is mediated by cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) (Thomas, 1995), which consist of two tyrosine-x-x-leucine (Y-x-x-L) pairs separated by 26 amino acids. Engagement of killer cell inhibitory receptors (KIRs) with clas,; I molecules induces tyrosine p h o s p h o r y l a t i o n ,of either tyrosine residue, and subsequent recruitment of the protein tyrosine phosphatase SHP-1 (Burshtyn et al., 1996; Olcese et al., 1996; Campbell et al., 1996; Fry et al., 1996; Binstadt et al., 1996). Some N K cell receptors lack the I T I M s due to a premature truncation o f the c y t o p l a s m i c tail and t h e r e f o r e do not mediate NK-cell inhibition. On the contrary, this group of receptors has a stimulatory function (Moretta et al., 1995 ; Biassoni et al., 1996).
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69th F O R U M I N I M M U N O L O G Y
W e h a v e n o w e x t e n d e d the n o t i o n o f I g - S F inhibitory receptors to myeloid antigen presenting cells (APCs), by identifying a new molecule, called Ig-like transcript 3 (ILT3) that negatiw:ly regulates APC functional responses triggered via stimulatory receptors (Colonna, unpublished). ILT3 is selectively expressed by dendritic cells (DCs), monocytes and macrophages. It consists of an extracellular region of 2 I g - S F domains and of a c y t o p l a s m i c region with 3 putative ITIMs, which are similar to those found in KIRs, thereby suggesting an inhibitory function of ILT3. Using anti-lLT3 mAbs, we have shown that ILT3 is a - 5 5 - 6 0 - k D a monomer, which is not N-glycosylated, but is constitutively phosphorylated. Coligation of ILT3 to stimulatory receptors expressed by APCs results in extinction of the increased [Ca2+] i triggered by these receptors. We have also tested whether ILT3 is used by APCs for antigen uptake. ILT3 is efficiently internalized and, furthermore, it delivers its ligand to an intracellular compartment, where it is processed and presented on M H C class II molecules. Thus, ILT3 is a novel inhibitory receptor with a dual function: it can negatively regulate activation of APCs and it can function for antigen capture and presentation.
The ligand of I L T 3 is still unknown. ILT3 is closely related to Fc receptors such as the human F c ~ R (Maliszewski et al., 1990), suggesting that ILT3 may be a new Fc receptor. However, we did not detect any significant binding of human monomeric and heat-aggregated IgM, IgG, IgA and IgE to ILT3 transfectants. ILT3 also shows h o m o l o g y to KIRs, and thus, it may be a receptor for MHC class I molecules. We have investigated this possibility by analysing binding of soluble I L T 3 - H u l g G 1 fusion protein to M H C class I transfectants in the class Ideficient mutants 721.221. However, no significant binding could be detected by FACS analysis under the same experimental conditions in which KIRHulgG fusion proteins bind to M H C ,class I molecules. We are investigating the possibility that ILT3 is a receptor for cell surface molecules related to MHC class I molecules, such as non-classical class I molecules [CD1 (Porcelli, 1995), MR1 (Hashimoto et al., 1995), MIC ( B a h r a m et al., 1994)] or for serum factors such as complement components.
It is noteworthy that ILT3 is expressed on DCs. These are a unique type of leukocytes whose primary function is to capture antigens, process them and present them to T cells (Steinman, 1991). While the uptake and the processing of antigen is a major function of DCs, yet only a few mechanisms and receptors specialized for antigen capture and presentation h a v e b e e n found to be e x p r e s s e d on D C s (Jiang et al., 1995; Sallusto et al., 1995; Bieber et al., 1992). Our data indicate that ILT3 is a unique receptor expressed in DCs, able to target the ligand into processing and peptide-loading compartments.
We thank S. Bahrain and M. Celia for critical reading of the manuscript. The Basel Institute for Immunology was founded and is supported by F. Hoffmann-La Roche Ltd., CH 4002 Basel, Switzerland.
Another interesting feature of ILT3 is the presence of alternatively spliced forms in different cell t y p e s . T h i s p h e n o m e n o n has b e e n p r e v i o u s l y observed for the FcyRIIB, which is expressed in B lymphocytes and in myeloid cells in two different isoforms, called FcyRIIB 1 and FcyRIIB2, respectively (Amigorena et al., 1992; Muta et al., 1994). These isoforms are generated by alternative splicing of sequences encoded by the first intracytoplasmic exon of the FcyRIIB gene and differ by a 19-amino acids insertion in human FcyRIIB 1 (47 amino acids in mouse FcyRIIB 1). This insertion does not modify the inhibitory function of FcyRIIB. However, it prevents both FcyRII-mediated endocytosis and FcyRII-mediated antigen presentation (Amigorena et at., 1992; Muta et al., 1994). Thus, only myeloid cells are c a p a b l e of F c y R I I B r e c e p t o r - m e d i a t e d endocytosis. Similarly, ILT3 alternatively spliced isoforms generated in different tissues m a y have different antigen p r e s e n t a t i o n and/or signalling capacities.
Acknowledgements
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