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Originally published online as doi:10.1189/jlb.0905537 on December 19, 2005

Published online before print December 19, 2005
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(Journal of Leukocyte Biology. 2006;79:417-424.)
© 2006 by Society for Leukocyte Biology

Fine-tuning of immune responses by SLAM-related receptors

Rauf Bhat, Philipp Eissmann, Johanna Endt, Sabrina Hoffmann and Carsten Watzl1

Institute for Immunology, University Heidelberg, Germany

1 Correspondence: Institute for Immunology, University Heidelberg, INF 305, 69120 Heidelberg, Germany. E-mail: carsten.watzl{at}urz.uni-heidelberg.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 THE CD150 (SLAM) RECEPTOR
 THE CD244 (2B4) RECEPTOR
 THE NTB-A RECEPTOR
 THE CD84, CD229 (Ly9),...
 EARLY SRR SIGNAL TRANSDUCTION
 OUTLOOK
 REFERENCES
 
The modulation of antigen receptor signals is important for a productive immune response. The main function of the recently identified members of the signaling lymphocyte activating molecule (SLAM)-related receptors (SRR) is the fine-tuning of immune cell activation. Disruption of SRR function is the cause for severe immune disorders such as X-linked lymphoproliferative syndrome (XLP), where XLP patients carry a mutation in SLAM-associated protein (SAP) (SH2D1A), an important adaptor molecule for the signal transduction of SRR. Recent data also suggest that SRR may play a role in autoimmune diseases and the function of hematopoietic stem and progenitor cells. Here, we review the current understanding of SRR function in different immune cells.

Key Words: T cells • NK cells • activation • costimulation • Th1/2 polarization


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
THE CD150 (SLAM) RECEPTOR
 THE CD244 (2B4) RECEPTOR
 THE NTB-A RECEPTOR
 THE CD84, CD229 (Ly9),...
 EARLY SRR SIGNAL TRANSDUCTION
 OUTLOOK
 REFERENCES
 
The engagement of the antigen receptor is essential for the activation of T or B lymphocytes. The signals following this event have been characterized extensively over the last two decades. Triggering the antigen receptor is not the only factor determining lymphocyte activity. Multiple other receptor ligand interactions are necessary for a productive activation of naïve lymphocytes [1 , 2 ]. These interactions can deliver costimulatory or inhibitory signals and are important for the fine-tuning of an immune response. The investigation of these modulating signals is the new challenge for understanding lymphocyte regulation.

The recently discovered family of signaling lymphocyte activating molecule (SLAM)-related receptors (SRR) [3 ] is a group of surface molecules whose main function seems to be the fine-tuning of lymphocyte responses. Members of this group of receptors are CD150 (SLAM), CD244 (2B4), CD84, CD229 (Ly-9), NTB-A (Ly-108), and CD319 {CD2-like receptor-activating cytotoxic cells (CRACC), CS1; Fig. 1 [3 4 5 6 7 ]}. SRR belong to the family of Ig-like receptors, exhibiting an extracellular domain with two or four Ig-like domains, and an intracellular domain with tyrosine-based signaling motifs, immunoreceptor tyrosine-based switch motif (ITSM) (Fig. 1) . The SRR genes are all clustered within a region of human chromosome 1q21-23. Although several members of the SRR were first discovered in NK cells, their expression can be found on many immune cells including NK, T, and B lymphocytes, macrophages, monocytes, DC, platelets, granulocytes, and hematopoietic stem and progenitor cells (Fig. 1) .


Figure 1
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  		Figure 1. SLAM-related receptor overview. ITSM, Immunoreceptor tyrosine-based switch motif; NAIL, natural killer (NK) cell activation-inducing ligand; TM, transmembrane domain; C2, C2-type immunoglobulin (Ig) domain; V, V-type Ig domain; T, T cell; Eo, eosinophils; Mono, monocytes; Baso, basophils; MPP, multipotent hematopoietic progenitors; B, B cell; DC, dendritic cells; M{phi}, macrophages; Plat, platelets; HSC, hematopoietic stem cells; Gran, granulocytes.

 
Almost all SRR family members, with the exception of CD244, serve as their own ligand through homophilic interactions [8 9 10 11 12 13 ]. CD244 interacts with CD48 [14 , 15 ], a glycosylphosphatidylinositol-anchored member of the CD2 family with broad expression in the hematopoietic system. Engagement of SRR can modulate the activity of different immune cells, demonstrating that this receptor family is engaged in the fine-tuning of immune responses. The importance of this function is underscored by severe immune disorders caused by the disruption of SRR function. Recent data indicate that a polymorphism in the SRR gene cluster is associated with the susceptibility to systemic lupus erythematosus in mice [16 ]. Another example is patients suffering from X-linked lymphoproliferative syndrome (XLP), a primary immunodeficiency, which was first characterized by an inappropriate immune response to Epstein-Barr virus (EBV) [17 ]. XLP patients carry a mutation in a gene encoding for SLAM-associated protein (SAP; SH2D1A) [18 , 19 ], an adaptor molecule that is important for the signal transduction of almost all SRR. Here, we will review the latest understanding of SRR function in different immune cells and will discuss how the dysfunction of SRR may be involved in the malfunction of immune responses. We will focus most of our attention on the human SRR, but also mouse data will be discussed.


   THE CD150 (SLAM) RECEPTOR
TOP
 ABSTRACT
 INTRODUCTION
 THE CD150 (SLAM) RECEPTOR
THE CD244 (2B4) RECEPTOR
 THE NTB-A RECEPTOR
 THE CD84, CD229 (Ly9),...
 EARLY SRR SIGNAL TRANSDUCTION
 OUTLOOK
 REFERENCES
 
CD150 (SLAM) was one of the first described members of the SRR [20 ]. Most of the research about CD150 function was done in T cells. CD150 is constitutively expressed on peripheral blood CD45ROhigh memory T cells, T cell clones, and immature thymocytes and can be up-regulated on naive T cells after activation [20 , 21 ]. Early studies suggested that antibody-mediated engagement of CD150 can enhance antigen-specific T cell proliferation, independent of CD28, and enhance interferon-{gamma} (IFN-{gamma}) production and shift the cytokine profile toward a T helper cell type 1 (Th1) phenotype [20 , 21 ]. Engagement of CD150 with agonistic antibodies during allergen-specific stimulation results in a stable shift of Th2 cell populations to IFN-{gamma}-producing Th0 and Th1 phenotypes in atopic dermatitis patients. Consequently, IgE synthesis by B cells is reduced, resulting from decreased production of interleukin (IL)-4 and IL-13 [22 ]. In line with the effect on Th1 function, CD150 expression is stronger in Th1 compared with Th2 cells [23 ]. These data suggested that antibody-mediated engagement of CD150 results in enhanced Th1 responses, which is important for cell-mediated immune responses to intracellular pathogens. Antibody-mediated stimulation of CD150 in patients with tuberculosis infection can enhance IFN-{gamma} production, and higher CD150 expression is associated with a significant Mycobacterium tuberculosis-dependent T cell proliferation and IFN-{gamma} production [24 , 25 ].

It is interesting that CD150-deficient mice suggest the contrary role of CD150 in Th1/Th2 polarization. CD150-deficient T cells show reduced IL-4 and IL-13 but slightly increased IFN-{gamma} production after T cell receptor (TCR) stimulation [26 , 27 ], suggesting that CD150 is actually necessary for driving Th2 cytokine production and would block IFN-{gamma} production in mouse T cells. This contradictory finding to the studies cited above cannot just be explained by differences between human and mouse CD150 function, as earlier reports also showed that antibody-mediated CD150 stimulation increases IFN-{gamma} production in mouse T cells [28 ]. The solution to this discrepancy could lay in the form of CD150 engagement used in many of these studies. Antibody-mediated CD150 engagement may fail to mimic the physiologic stimulation of CD150 by actually blocking the homophilic CD150 interaction between T cells. SLAM signaling can indeed inhibit IFN-{gamma} production during T cell activation [29 ], and blocking its engagement would therefore result in increased IFN-{gamma} production, as observed in the studies mentioned above. An alternative explanation could be that other SRR compensate for CD150 deficiency in CD150–/– mice. Conditional CD150 knockout (KO) mice, physiologic stimulation with CD150-expressing cells, and small interfering RNA-mediated down-modulation of CD150 in human T cells will be necessary to finally solve this discrepancy.

CD150 costimulation also enhances the cytotoxic activity of T cells [30 , 31 ]. Up-regulation of CD150 expression after T cell activation can be observed in many different T cell subsets including cytotoxic CD8, Th1, Th2, CD4+ CD25+ regulatory T cells, and cytokine-induced killer cells [23 , 30 31 32 ]. Up-regulation of CD150 can be used as a marker for cellular activation as seen in rheumatoid arthritis patients [33 ]. As CD150 is its own ligand, activation-induced up-regulation may result in T cell costimulation by engagement of CD150 between T cells. However, also, antigen-presenting cells (APC) express CD150. DC up-regulate CD150 expression after Toll-like receptor (TLR) triggering, CD40 ligand activation, or IL-1ß stimulation [34 , 35 ]. CD150 can therefore be engaged during the contact between T cells and APC and lead to efficient T cell costimulation. DC can also be stimulated during this process: Engagement of CD150 enhances IL-12 and IL-8 production by DC [34 ]. Likewise, CD150 expression can be induced on monocytes by TLR stimulation [36 ], and CD150 controls the production of IL-12, tumor necrosis factor (TNF), and nitric oxide (NO) in response to lipopolysaccharide (LPS) by macrophages, as shown in CD150-deficient mice [27 ]. This demonstrates that CD150 engagement can costimulate TLR4 signal transduction in macrophages.

B lymphocytes also express CD150, and CD150 stimulation can enhance B cell proliferation and Ig synthesis [37 , 38 ]. Homophilic SLAM signaling induced during B and T cell interactions can therefore amplify the humoral immune response. Recently, SLAM and CD84 were detected on platelets and shown to promote platelet aggregation [39 ]. SLAM-deficient mice suffer from an overall defect in platelet aggregation in vitro and a delayed arterial thrombotic process in vivo [39 ].


   THE CD244 (2B4) RECEPTOR
TOP
 ABSTRACT
 INTRODUCTION
 THE CD150 (SLAM) RECEPTOR
 THE CD244 (2B4) RECEPTOR
THE NTB-A RECEPTOR
 THE CD84, CD229 (Ly9),...
 EARLY SRR SIGNAL TRANSDUCTION
 OUTLOOK
 REFERENCES
 
CD244 was first described on mouse NK cells as a triggering receptor for non-major histocompatibility complex (MHC)-restricted cytotoxicity [40 ]. Ligation of the CD244 receptor on human NK cells by antibodies or interaction with its ligand CD48 on sensitive target cells induces cytotoxicity and IFN-{gamma} release [41 42 43 44 45 ]. CD244 also has important costimulatory functions by modulating or enhancing other activating NK cell signals [46 ]. The activation of NK cells through the interaction of CD244 with CD48 is controlled by inhibitory receptors, which recognize self-MHC class I molecules, as coligation of CD244 with inhibitory receptors strongly reduces CD244-mediated signals [4 , 47 , 48 ]. It is interesting that under certain circumstances, human CD244 can also transmit inhibitory signals. At early stages of NK cell development, the expression of activating receptors precedes the expression of inhibitory receptors at a time when the NK cell cytotoxic activity increases strongly. On these NK cell precursors, CD244 functions as an inhibitory receptor, thereby ensuring the self-tolerance of these cells [49 ]. Similarly, CD244 engagement on NK cells isolated from human lymph nodes can inhibit IFN-{gamma} production [50 ], suggesting that CD244 may have opposing functions on NK cells from peripheral blood and secondary lymphoid organs. It is interesting to note that DC found in inflamed lymph nodes lack CD48 expression [50 ], which would avoid a negative influence of CD244 engagement on NK cell function during the NK/DC cross-talk in lymph nodes.

Although mouse CD244 was first described as an activating NK cell receptor [40 ], recent data suggest that the opposite may be true. An inhibitory function of CD244 in mouse NK cells is supported by the generation of CD244-deficient mice [51 , 52 ]. NK cells derived from these mice show increased killing and production of IFN-{gamma} when stimulated by CD48-expressing target cells. They also display an increased in vivo clearance of CD48-positive tumor cells [51 ], suggesting that the interaction between CD244 and CD48 induces a negative signal in mouse NK cells. In addition, it was shown that CD244 accumulates preferentially at the noncytolytic immune synapse in mouse NK cells [52 ]. However, there is evidence that the phenotype of CD244 deficiency is gender-specific, as the function of NK cells derived from male CD244–/– mice is not changed [53 ], complicating the interpretation of the results. In mice, some immature and a subset of mature NK cells lack inhibitory receptors for self-MHC class I. The self-tolerance of these cells is most probably maintained by a newly defined class of inhibitory receptors, which do not depend on the recognition of self-MHC class I [54 , 55 ]. Experiments in CD244-deficient mice indicate that CD244 might participate in this process of non-MHC-dependent suppression [56 ]. Contrary to these data, a recent report demonstrated that CD244 is responsible for the elimination of CD48-positive tumor cells in mice [57 ]. This activating function of CD244 is shifted toward inhibition in NK cells from SAP-deficient mice, a molecule that is important for CD244 signaling as discussed below. These findings could mean that mouse CD244 is not inhibitory per se but rather that the functional consequence of CD244 engagement depends on the differential expression of molecules that mediate CD244 signaling [57 , 58 ]. Alternatively, CD244 could have different functions on different NK cell subsets as described above for human peripheral blood and lymph node NK cells. Also, mouse CD244 is expressed in two isoforms, differing in the length of their cytoplasmic tail [59 ]. Only the long form of CD244 seems capable of mediating inhibitory signals [51 ], and an earlier report suggests an activating function for the short form of CD244 [60 ]. Differential expression of these isoforms could therefore also account for the different outcome of CD244 triggering observed in the reports mentioned above.

CD244 and its ligand CD48 are both expressed on NK cells, and the interaction of CD48 and CD244 between NK cells can enhance NK cell proliferation in response to IL-2 [61 ]. The importance of this CD244-CD48 interaction between NK cells is supported by observations in CD244-deficient mice, which display a defect in the development of NK cell effector functions [62 ], suggesting that CD244 mediates a positive signal under these conditions. One explanation for the positive and negative function of mouse CD244 could be that CD244 exerts different signals during the interactions between NK cells or the interaction between NK and other cells [63 ]. In human NK cells, the CD244-CD48 interaction between NK cells does not seem to be necessary for NK cell function (Sebastian Stark, C. Watzl, unpublished data).

The interaction of CD244 expressed on NK cells with CD48 expressed on other hematopoietic cells does not transmit signals in one direction only. The expression of CD244 on murine NK cells costimulates CD8+ T cells via CD48 [61 ]. The importance of CD244 serving as a ligand to stimulate cells through CD48 is highlighted by the finding that human NK cell cytotoxicity can be stimulated by CD244-expressing target cells (ref. [64 ] and Birgitta Messmer, C. Watzl, unpublished data).

Much less is known about the function of 2B4 on other immune cells. The expression of CD48 and CD244 on murine CD8+ T cells results in costimulatory signals that increase proliferation and antigen-specific cytotoxicity [65 , 66 ]. It is proposed that the function of CD244 in this interaction is most likely to serve only as the ligand for CD48. In addition to its role as a ligand, CD244 is pivotal as a costimulatory receptor on CD8+ T cells to mount an adequate cytolytic T lymphocyte response against EBV-infected B cells [67 , 68 ]. Stimulation of CD244 on eosinophils enhances the release of peroxidase, IFN-{gamma}, and IL-4, as well as the cytotoxic response of these cells [69 ].


   THE NTB-A RECEPTOR
TOP
 ABSTRACT
 INTRODUCTION
 THE CD150 (SLAM) RECEPTOR
 THE CD244 (2B4) RECEPTOR
 THE NTB-A RECEPTOR
THE CD84, CD229 (Ly9),...
 EARLY SRR SIGNAL TRANSDUCTION
 OUTLOOK
 REFERENCES
 
Engagement of NTB-A on human NK cells by antibody-mediated cross-linking, NTB-A fusion proteins, or homophilic interaction with NTB-A-expressing cells stimulates cytotoxicity and proliferation, as well as IFN-{gamma} and TNF-{alpha} production [5 , 11 , 12 ]. NTB-A is therefore a positive regulator of NK cell function. Similar to the CD244 receptor, NTB-A can effectively costimulate other activating NK cell signals [5 ]. The stimulatory function of NTB-A is defective in XLP patients. It is interesting that triggering of NTB-A in these patients with defective SAP expression results in the inhibition of NK cell function [5 ].

NTB-A engagement on CD4+ T cells can substitute for the CD28 costimulatory pathway. Costimulation of Th cells by NTB-A results in proliferation and IFN-{gamma} but not IL-4 secretion, suggesting a role for NTB-A in Th1 polarization [70 ]. This is supported by experiments in which injection of NTB-A Fc-fusion protein, which blocks the homophilic interaction of NTB-A, reduced the Th1 cytokine-induced isotype switch to IgG2a and IgG3 in mice. Furthermore, it delayed the onset of Th1-mediated experimental allergic encephalomyelitis [70 ].

In contrast to the above data, experiments from mice with a targeted disruption of the NTB-A gene propose a role for NTB-A in Th2 polarization [71 ]. These mice bear a deletion of the two Ig-like domains (Ly108{Delta}E2+3), which results in the loss of the complete extracellular domain of NTB-A and hence, most likely, in a complete loss of NTB-A function. The absence of functional NTB-A disrupts IL-4, but not IFN-{gamma} production, as determined by in vitro and in vivo experiments [71 ]. This is reminiscent of the data for CD150, where in vitro data in human cells suggest a role in Th1 polarization, and KO mice suggest a role in Th2 polarization.

NTB-A KO animals are also more susceptible to bacterial infections, which is a consequence of a defective production of reactive oxygen species by neutrophils [71 ]. These findings demonstrate the importance of NTB-A function, not only in adaptive but also in innate immunity.


   THE CD84, CD229 (Ly9), AND CD319 (CRACC, CS1) RECEPTORS
TOP
 ABSTRACT
 INTRODUCTION
 THE CD150 (SLAM) RECEPTOR
 THE CD244 (2B4) RECEPTOR
 THE NTB-A RECEPTOR
 THE CD84, CD229 (Ly9),...
EARLY SRR SIGNAL TRANSDUCTION
 OUTLOOK
 REFERENCES
 
Little is known about the function of CD84, CD229, and CD319 in the fine-tuning of lymphocyte function. Similar to CD150 or NTB-A, CD84 can exert an activating effect as a coreceptor on CD3-positive lymphocytes. T cells stimulated with CD84 and CD3 display enhanced production of IFN-{gamma} and increased proliferation [9 , 72 ]. The effect on proliferation activity does not seem to be influenced by the presence of SAP, as it also occurs in XLP patients [72 ]. It will be interesting to see if CD84 KO mice confirm or contradict the Th1 polarization by CD84 costimulation. CD84 is also expressed highly in certain B cell subsets [73 , 74 ], but a functional role of CD84 for these lymphocytes is not defined so far. In platelets, CD84 can induce microaggregate formation, and CD84 together with CD150 are important for platelet aggregate stability [39 ].

In contrast to other SRR, CD229 engagement appears to have a negative effect on TCR signaling. Ligation of CD229 on CD3-stimulated T cells decreases cytokine release and proliferation [75 ]. Surface expression of CD229 is reduced after TCR or BCR signaling through endocytosis of CD229 via clathrin-coated pits [76 ]. This could be a control mechanism to limit the effect of CD229 on T cell stimulation and is likely mediated by phosphorylation of CD229, allowing Grb2 recruitment and favoring the endocytosis of the receptor [75 ]. CD229 is also found in the contact area between T and B cells, but no functional consequences of this interaction have been described so far [13 ].

Although CD319 is expressed widely in cells of lymphoid origin, its only known function to date is restricted to NK cells. CD319 acts as an activating receptor enhancing NK cell cytotoxicity [6 , 10 ]. Signaling of CD319 occurs independently of SAP but through engagement of the extracellular signal-regulated kinase (ERU) pathway [6 ].


   EARLY SRR SIGNAL TRANSDUCTION
TOP
 ABSTRACT
 INTRODUCTION
 THE CD150 (SLAM) RECEPTOR
 THE CD244 (2B4) RECEPTOR
 THE NTB-A RECEPTOR
 THE CD84, CD229 (Ly9),...
 EARLY SRR SIGNAL TRANSDUCTION
OUTLOOK
 REFERENCES
 
The data described above establish a clear role for SRR in the fine-tuning of immune responses. How do SRR mediate their effects inside the cell? SRR carry a characteristic signaling motif within their cytoplasmic tail, ITSM (Fig. 1) , which enables these receptors to recruit a group of cytoplasmic adaptor molecules. Members of this group are SAP (also called SH2D1A), EWS-activated transcript 2 (EAT-2; also called SH2D1B), and EAT-2-related transducer (ERT; also called SH2D1C) [58 , 77 ]. All are composed of a Src homology 2 (SH2) domain linked to a short C-terminal tail. SAP was identified as being mutated in XLP patients [18 , 19 ]. EAT-2 was first identified as a transcript, which was aberrantly expressed in fibroblasts transformed by the Ewing’s sarcoma-associated oncogene EWS-FL11 [78 ]. ERT is only expressed in mouse NK cells [58 ]. In humans, the gene encoding ERT has apparently evolved into a noncoding pseudogene and is not functional. It is interesting that the expression and regulation of these adaptor molecules are different from the SRR. Although the expression of several SRR is up-regulated after T cell activation, SAP expression is reduced following T cell stimulation [79 ]. IL-2 stimulation of human NK cells does not significantly affect the expression of CD244 or NTB-A but increases SAP expression and reduced EAT-2 expression (J. Endt, P. Eissmann, and C. Watzl, unpublished data). This suggests that SRR may mediate their effects by coupling to different adaptor molecules depending on the cell type and the state of activation.

SAP binds to the sequence TIpYxxV/I (single amino acid code) [80 ]. This sequence is found in one or more copies in all SRR except CD319, explaining why this receptor may function independently of SAP [6 ]. Insights into the mechanism of SAP function were given by the finding that it has the capacity to couple SRR to the Src-related protein tyrosine kinase FynT (the hematopoietic-specific isoform of Fyn) [81 , 82 ]. This binding is mediated by the interaction of a second binding surface around arginine 78 in the SAP SH2 domain to the SH3 domain of FynT. The recruitment of FynT is essential for the function of SAP, as shown by mutating arginine 78 [26 , 83 ]. EAT-2 and ERT do not contain this arginine 78-based motif, and it is therefore expected that they signal by an alternative mechanism.

SAP plays a pivotal role in SRR signaling, as shown by cells lacking functional SAP expression, such as in patients with XLP [84 , 85 ] or SAP KO mice [86 , 87 ]. XLP is a primary immunodeficiency, which was first characterized by an inappropriate immune response to EBV [17 ]. After EBV infection, ~50% of XLP patients develop fatal mononucleosis with an uncontrolled proliferation of B and T cell populations. Twenty-five percent develop hypogammaglobulinemias, common variable immunodeficiencies, and malignant B cell lymphomas. As SAP can couple to almost all SRR, many SRR show defective function in XLP patients or SAP-deficient mice. Therefore, the mechanisms underlying the XLP phenotype are likely to be complex. In the following, we will review the impact of SAP deficiency on the function of several SRR.

CD150 function is critically dependent on SAP expression. SAP-deficient mice show a similar T cell phenotype as CD150 KO mice [26 , 27 , 86 , 87 ]. In the absence of SAP, CD150-induced T cell proliferation is defective, and Th2 cytokine production is impaired, again suggesting that CD150 is important for Th2 polarization in mice [86 , 87 ]. CD244-mediated NK cell activation is also defective in XLP patients [88 89 90 91 ]. CD244 phosphorylation and signal transduction seem to be dependent on SAP and the recruitment of FynT [57 , 83 ]. It is interesting that one group even reported that similar to NTB-A, CD244 induces NK cell inhibition in the absence of SAP [88 ]. In addition to recruiting FynT, SAP may function as a blocker of SH2 domain-interactions, preventing negative-regulating signaling molecules such as SH2-containing tyrosine phosphatase-1 (SHP-1), SHP-2, or Csk from associating with phosphorylated CD244 [45 , 92 ]. This could explain the finding that in the absence of functional SAP, CD244 is not only unable to lead to NK cell activation but is actually inhibiting NK cells [88 ]. Likewise, early precursors of human NK cells are devoid of SAP, which could explain why CD244 is also inhibitory in these cells [49 ].

The inhibitory function of CD244 in the absence of SAP is not sufficient to explain the finding’s recent reports, which demonstrated that mouse CD244 is inhibitory even in the presence of SAP [51 ]. Differential regulation of other SAP-like adaptors such as EAT-2 and ERT could solve this issue. EAT-2 and ERT can act as negative regulators of NK cell function in mice, as shown by EAT-2 and ERT KO animals [58 ]. The inhibitory function of both adaptors seems to be dependent on the phosphorylation of two tyrosines in the C terminus of both molecules. Mutational analysis revealed that this phosphorylation is important for the negative function of EAT-2 and ERT but does not influence the binding capacity to CD244 [58 ]. This supports the idea that EAT-2 and ERT inhibit NK cell function by an active but unknown signaling mechanism rather than by displacing SAP from CD244. This could be a plausible explanation for the dual function of CD244. SAP mediates the activating function of CD244 via the recruitment of FynT, whereas binding of EAT-2 and ERT may mediate the inhibitory function. ERT does not exist in humans, and human EAT-2 only contains one tyrosine in its C terminus. Our recent results actually indicate that EAT-2 may play a positive role for the signaling of the human NTB-A receptor (P. Eissmann, C. Watzl, unpublished results). This could explain why human CD244 is an activating receptor and is only inhibitory under certain conditions and only in the absence of SAP. In this case, other negatively regulating molecules, such as SHP-1, SHP-2, SH2 domain containing inositol phosphatase, or Csk, may interact with CD244 in the absence of SAP-related adaptors and could induce the inhibitory signaling cascade of the CD244 receptor [92 ].

Several functions of the SRR are also independent of SAP-related adaptors. CD84-induced T cell proliferation and CD319-induced NK cell cytotoxicity are unaffected in XLP patients, suggesting that they are independent of SAP [6 , 72 ]. Human CD244 can recruit the adaptor molecule 3BP2 independently of SAP binding [93 ]. This association can enhance 2B4-mediated cytotoxicity but not cytokine secretion through the phosphorylation of Vav-1 [93 ].


   OUTLOOK
TOP
 ABSTRACT
 INTRODUCTION
 THE CD150 (SLAM) RECEPTOR
 THE CD244 (2B4) RECEPTOR
 THE NTB-A RECEPTOR
 THE CD84, CD229 (Ly9),...
 EARLY SRR SIGNAL TRANSDUCTION
 OUTLOOK
REFERENCES
 
The accumulated data during the past years have clearly established an important role for SRR during the fine-tuning of immune responses as reviewed above (Table 1 ). This is exemplified impressively in XLP patients, where the malfunction of SRR is the basis for severe immune disturbances. The immune defects seen in XLP patients are likely the result of the dysfunction of several SRR, which makes it difficult to understand the pathology of XLP in detail. The careful analysis of SRR function in various cell types and the cross-talk between different SRR will likely give a better understanding and insight into the malfunction of the immune response in XLP patients. Animal models are useful tools to study the function of SRR in vivo. However, there are striking discrepancies between the results of in vitro SRR stimulation experiments and SRR KO mice. CD150 and NTB-A were described to have a Th1-polarizing effect. CD150 and NTB-A-deficient mice suggest the opposite and show that these receptors are needed for Th2 polarization. Also, CD84 seems to favor Th1 cytokine production. It will be interesting to see if CD84 KO animals demonstrate the opposite. CD244 was described as an activating NK cell receptor. KO animals have now established the opposite role and demonstrated that CD244 is an inhibitory receptor. The reasons for these obvious discrepancies can only be explained partially by experimental differences as described above.


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  		Table 1. SLAM-Related Receptor Functions

 
One interesting aspect that may help to solve this issue is the finding that SRR are differentially expressed on hematopoietic precursors [94 ]. Hematopoietic stem cells express CD150, and multipotent hematopoietic progenitors are CD150– and CD244+. The most restricted multipotent hematopoietic progenitors then also acquire CD48 expression [94 ]. The combinatorial expression of SRR is the only marker to precisely distinguish stem and progenitor cells. Besides this function as a marker, SRR may also be engaged during the contact between these cells or during the interaction with stroma cells. This makes it possible that SRR also play a role in hematopoietic progenitor function and leukocyte development. Such a role was reported recently for NKT cells. These cells are absent in XLP patients and SAP-deficient mice [95 96 97 ], suggesting that the SAP-dependent signals of one or more SRR are essential for the development of NKT cells. This function of SRR during the development of leukocytes could also influence the phenotype of KO animals. Conditional KO strategies could eliminate such effects.

SRR may also be involved in autoimmune diseases such as systemic lupus erythematosus (SLE). A polymorphism in the SRR gene cluster on mouse chromosome 1 is associated with the susceptibility to mouse lupus [16 ]. Although several SRR may be involved in the development of autoimmune diseases, a specific isoform of NTB-A is expressed constitutively in susceptible mouse strains [16 ]. Enhanced T cell costimulation by this NTB-A isoform may be the cause of the observed autoimmunity. It is interesting that SAP deficiency protects mice from an experimental model of lupus [98 ], again implicating SRR in the development of SLE. This underscores the importance of SRR for the regulation of immune responses.

We are just beginning to understand the function of the SRR. Their differential signaling, depending on the expression and regulation of SAP-related adaptors and other signaling molecules, creates a complex network of effects in a variety of immune cells. In addition to understanding the intracellular signaling pathways of the SRR, it will be important to determine how SRR are triggered during immune reactions. Although their homophilic interaction may mediate receptor stimulation among neighboring cells of the same type, SRR can also be engaged during the contact of different immune cells. Defining these interactions in the future will greatly improve our understanding of SRR function in normal and pathological immune responses.


   ACKNOWLEDGEMENTS
 
Our research is supported by grants from the Deutsche Forschungsgemeinschaft (SFB405, A9), the Deutsche Krebshilfe, and the BioFuture program of the BMBF.

Received September 29, 2005; revised November 25, 2005; accepted November 26, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 THE CD150 (SLAM) RECEPTOR
 THE CD244 (2B4) RECEPTOR
 THE NTB-A RECEPTOR
 THE CD84, CD229 (Ly9),...
 EARLY SRR SIGNAL TRANSDUCTION
 OUTLOOK
 REFERENCES
 

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