SLAM-associated Protein Research Articles

Antigen-specific responses and ANA production in B6. Sle1b mice: A role for SAP

B6. Sle1b mice, which contain the Sle1b gene interval derived from lupus prone NZM2410 mice on a C57BL/6 background, present with gender-biased, highly penetrant anti-nuclear antibody (ANA) production. To obtain some insight into the possible induction mechanism of autoantibodies in these mice we compared antigen-specific T dependent (TD) and T independent (TI-II) responses between B6. Sle1b and B6 mice before the development of high ANA titers. Our results show that B6. Sle1b mice mount enhanced responses to a TI-II antigen. Additionally, the memory T cell response generated by a TD antigen also increased. This enhancement correlates with the greater ability of B cells from B6. Sle1b mice to present antigen to T cells. The SLAM Associated Protein (SAP) is critical for signaling of many of the molecules encoded by the SLAM/CD2 gene cluster, candidates for mediating the Sle1b phenotype; therefore, we also investigated the effect of sap deletion in these strains on the TD and TI-II responses as well as on ANA production. The results of these studies of responses to non-self-antigens provide further insight into the mechanism by which responses to self-antigens might be initiated in the context of specific genetic alterations.

SAP Enables T Cells to Help B Cells by a Mechanism Distinct from Th Cell Programming or CD40 Ligand Regulation

Genetic mutations disrupting the function of signaling lymphocytic activation molecule-associated protein (SAP) lead to T cell intrinsic defects in T cell-dependent Ab responses. To better understand how SAP enables Th cells to help B cells, we first assessed whether molecules important for B cell help are dysregulated in SAP-deficient (SAP knockout (KO)) mice. CD40 ligand (CD40L) expression was enhanced on unpolarized SAP KO T cells; however, Th2 polarization returned their CD40L expression to wild-type levels without rescuing their ability to help B cells. CD40L also localized normally to the site of contact between SAP KO T cells and Ag-bearing B cells. Finally, CD40L-deficient Th cells and SAP KO Th cells differed in their abilities to help B cells in vitro. These data argue that Ab defects caused by SAP deficiency do not result from a loss of CD40L regulation or CD40L function on CD4 T cells. SAP KO Th cells additionally displayed normal patterns of migration and expression of ICOS and CXCR5. Global gene expression was remarkably similar in activated SAP KO vs wild-type T cells, prompting us to investigate whether SAP is necessary for "programming" T cells to become B cell helpers. By restricting SAP expression during differentiation, we determined that SAP is not required during the first 5 days of T cell activation/differentiation to generate Th cells capable of helping B cells. Instead, SAP is necessary for very late stages of differentiation or, most likely, for allowing Th cells to communicate during cognate T:B interactions.

Differential Requirement for the SAP-Fyn Interaction during NK T Cell Development and Function

The adaptor molecule SAP (signaling lymphocytic activation molecule-associated protein) plays a critical role during NK T (NKT) cell development in humans and mice. In CD4(+) T cells, SAP interacts with the tyrosine kinase Fyn to deliver signals required for TCR-induced Th2-type cytokine production. To determine whether the SAP-dependent signals controlling NKT cell ontogeny rely on its binding to Fyn, we used the OP9-DL1 system to initiate structure function studies of SAP in murine NKT cell development. In cultures containing wild-type (WT) hematopoietic progenitors, we noted the transient emergence of cells that reacted with the NKT cell-specific agonist alpha-galactosyl ceramide and its analog PBS57. Sap(-/-) cells failed to give rise to NKT cells in vitro; however, their development could be rescued by re-expression of WT SAP. Emergence of NKT cells was also restored by a mutant version of SAP (SAP R78A) that cannot bind to Fyn, but with less efficiency than WT SAP. This finding was accentuated in vivo in Sap(R78A) knock-in mice as well as Sap(R78A) competitive bone marrow chimeras, which retained NKT cells but at significantly reduced numbers compared with controls. Unlike Sap(R78A) CD4(+) T cells, which produce reduced levels of IL-4 following TCR ligation, alpha-galactosyl ceramide-stimulated NKT cells from the livers and spleens of Sap(R78A) mice produced Th2 cytokines and activated NK cells in a manner mimicking WT cells. Thus, SAP appears to use differential signaling mechanisms in NKT cells, with optimal ontogeny requiring Fyn binding, while functional responses occur independently of this interaction.

Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

The signaling lymphocytic activation molecule family of receptors has been implicated in the pathophysiology of autoimmunity in humans and mice. One member of the family, Ly108, was strongly linked to lupus susceptibility in mice. High expression of a Ly108 isoform, Ly108-1, was observed in lymphocytes of lupus-prone mice. Herein, we examined the molecular basis for the influence of Ly108 on lupus susceptibility by studying Ly108 signal transduction in T cells. We observed that Ly108 was able to mediate a tyrosine phosphorylation signal implicating Ly108, Vav-1, and c-Cbl in a manner strictly dependent on engagement of the extracellular domain of Ly108 and co-expression of the Src homology 2 (SH2) domain-containing adaptor signaling lymphocytic activation molecule (SLAM)-associated protein (SAP). Evaluation of T cells from mice carrying mutations in the SAP-FynT pathway indicated that Ly108-triggered protein tyrosine phosphorylation was due to the capacity of SAP to recruit FynT. Importantly, Ly108-1 was more apt at triggering tyrosine phosphorylation signals in T cells when compared with the predominant Ly108 isoform found in non-lupus-prone mice, Ly108-2. This difference was due in part to the presence in Ly108-1 of a unique intra-cytoplasmic tyrosine-based motif that promoted Ly108 signal transduction. Together these data provided a molecular explanation for the involvement of Ly108 in lupus susceptibility in mice.

Molecular Basis of the Dual Functions of 2B4 (CD244)

2B4 belongs to the CD2 family of molecules and is expressed on all NK, gammadelta, and memory CD8(+) (alphabeta) T cells. The murine NK receptor 2B4 exhibits both inhibitory and activating functions, whereas human 2B4 has been reported to be an activating molecule. How murine 2B4 can act both as an activating and inhibitory receptor and what distinguishes its function from human 2B4 have remained largely unknown. We use here a model system that allows the study of human and murine 2B4 under identical and controlled conditions. These studies reveal that both human and mouse 2B4 can activate or inhibit NK cells. We show here that the level of 2B4 expression and the degree of 2B4 cross-linking play a significant role in the regulation of signaling lymphocyte activation molecule-associated protein-mediated activation by 2B4. A high level of 2B4 expression, heavy cross-linking, and relative paucity of signaling lymphocyte activation molecule-associated protein promote inhibitory function. Our studies demonstrate how a single receptor can have opposing function depending on the degree of receptor expression, extent of its ligation, and the relative abundance of certain adaptor molecules. Because the levels of 2B4 and CD48 are dynamically regulated, these findings have implications for the regulation of NK cell function.

Defining the Specificity Space of the Human Src Homology 2 Domain

Src homology 2 (SH2) domains are the largest family of interaction modules encoded by the human genome to recognize tyrosine-phosphorylated sequences and thereby play pivotal roles in transducing and controlling cellular signals emanating from protein-tyrosine kinases. Different SH2 domains select for distinct phosphopeptides, and the function of a given SH2 domain is often dictated by the specific motifs that it recognizes. Therefore, deciphering the phosphotyrosyl peptide motif recognized by an SH2 domain is the key to understanding its cellular function. Here we cloned all 120 SH2 domains identified in the human genome and determined the phosphotyrosyl peptide binding properties of 76 SH2 domains by screening an oriented peptide array library. Of these 76, we defined the selectivity for 43 SH2 domains and refined the binding motifs for another 33 SH2 domains. We identified a number of novel binding motifs, which are exemplified by the BRDG1 SH2 domain that selects specifically for a bulky, hydrophobic residue at P + 4 relative to the Tyr(P) residue. Based on the oriented peptide array library data, we developed scoring matrix-assisted ligand identification (or SMALI), a Web-based program for predicting binding partners for SH2-containing proteins. When applied to SH2D1A/SAP (SLAM-associated protein), a protein whose mutation or deletion underlies the X-linked lymphoproliferative syndrome, SMALI not only recapitulated known interactions but also identified a number of novel interacting proteins for this disease-associated protein. SMALI also identified a number of potential interactors for BRDG1, a protein whose function is largely unknown. Peptide in-solution binding analysis demonstrated that a SMALI score correlates well with the binding energy of a peptide to a given SH2 domain. The definition of the specificity space of the human SH2 domain provides both the necessary molecular basis and a platform for future exploration of the functions for SH2-containing proteins in cells.

High Level EBV Persistence in the IgM+ IgD+ CD27+ B Cell Subset in Patients with X-Linked Lymphoproliferative Disease Lacking Isotype-Switched Memory B Cells.

Epstein-Barr virus (EBV) infects >90% of population world wide and, in healthy virus carriers, establishes life long persistence in the immunoglobulin (Ig)Dneg, CD27+ (“class-switched”) memory B cell compartment normally produced by antigen stimulation and transit through germinal centres. Patients with the X-linked lymphoproliferative disease (XLP) cannot make such class-switched memory B cells due to an inherited mutation in the slam-associated protein (SAP) gene involved in the maturation of antibody responses. Interestingly, XLP patients are highly susceptible to severe primary EBV infection and develop a fulminant infectious mononucleosis (IM) which is often fatal and where the symptoms progress to resemble those of a different (non-familial) disease, EBV-associated haemophagocytosis syndrome (EBV-AHS), caused by virus entry into the NK or T cell system. Some XLP patients survive their primary infection, but the nature of EBV carriage in these individuals (lacking conventional memory B cells) remains unresolved. To investigate this further we obtained blood samples from 8 such XLP patients. EBV load in total peripheral blood mononuclear cells (PBMC), determined by quantitative PCR, occupied a broad range but on average was 2 to 3-fold fold higher than that of healthy controls. The virus was concentrated within the B cell (CD19+) compartment, as in healthy carriers, and not within T or NK cells, as typically seen in EBV-AHS. We then confirmed that these XLP patients indeed lacked conventional class-switched memory B cells but did carry a small population of IgM+, IgD+, CD27+ (“non-switched”) memory cells; however their circulating B cell pool was dominated by naïve (IgM+, IgD+, CD27neg) cells and by expanded numbers of immature “transitional” (CD10+ CD27neg) cells. In each of 4 cases studied by cell sorting, EBV was concentrated in this small subset of “non-switched” memory B cells. To see if the high virus load detected in these patients indicated true virus persistence as opposed to recent or recurrent infection, serial samples obtained over a 3 year period from two XLP patients were assayed. Virus load was stable and, in one case with the highest load, screening with markers of virus polymorphism detected the same resident strain over time. Our results in XLP patients make it clear that EBV can persist in the absence of a conventional class-switched memory B cell compartment. Instead, the virus is sequestered in a small population of “non-class-switched memory” cells with Ig gene mutations. The origin of such cells, which are also detectable in the blood of normal donors, is uncertain; however their existence in XLP patients suggests that such cells arise independently of germinal centre activity and hence that EBV may be able to colonise its host without exploiting germinal centre transit.

Analysis of genetic defects in patients with the common variable immunodeficiency phenotype in a single Taiwanese tertiary care hospital

Seven known genetic defects, including Bruton tyrosine kinase (Btk), CD4OL, and signaling lymphocyte activation molecule-associated protein (SAP) (all X-linked) and inducible costimulator molecule (ICOS), transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI), B-cell-activating factor of the tumor necrosis family receptor (BAFFR), and CD19 (all autosomal recessive), were found in patients with the phenotype of common variable immunodeficiency (CVID). To investigate these 7 candidate protein expressions and candidate gene sequences for comprehensive analysis of known genetic defects in patients with CVID. These 7 candidate protein expressions were evaluated by flow cytometry or Western blot, and candidate genes were evaluated by direct sequencing. Of 9 CVID patients from a single Taiwanese tertiary care hospital, we identified 2 cousins with decreased Btk expression who had a mutated (Asp521Val) kinase domain of Btk (1694A>T in exon 15) and 1 patient with decreased CD40L expression who had a mutated (Thr254Met) extracellular domain of CD40L (782T>C in exon 5). This comprehensive approach revealed that, in Taiwan, in some patients mild forms of X-linked agammaglobulinemia and hyper-IgM syndrome caused the CVID phenotype. No mutations of SAP, ICOS, TACI, BAFFR, and CD19 were identified in this study, although selection bias among the small study population and genetic variation may exist.

Homotypic Interactions Mediated by Slamf1 and Slamf6 Receptors Control NKT Cell Lineage Development

Commitment to the T and natural killer T (NKT) cell lineages is determined during alphabeta T cell receptor (TCR)-mediated interactions of common precursors with ligand-expressing cells in the thymus. Whereas mainstream thymocyte precursors recognize major histocompatibility complex (MHC) ligands expressed by stromal cells, NKT cell precursors interact with CD1d ligands expressed by cortical thymocytes. Here, we demonstrated that such homotypic T-T interactions generated "second signals" mediated by the cooperative engagement of the homophilic receptors Slamf1 (SLAM) and Slamf6 (Ly108) and the downstream recruitment of the adaptor SLAM-associated protein (SAP) and the Src kinase Fyn, which are essential for the lineage expansion and differentiation of the NKT cell lineage. These receptor interactions were required during TCR engagement and therefore only occurred when selecting ligands were presented by thymocytes rather than epithelial cells, which do not express Slamf6 or Slamf1. Thus, the topography of NKT cell ligand recognition determines the availability of a cosignaling pathway that is essential for NKT cell lineage development.

The SLAM-Associated Protein Signaling Pathway Is Required for Development of CD4 + T Cells Selected by Homotypic Thymocyte Interaction

MHC class II-expressing double-positive thymocytes induce progression of CD4(+) T cell development as efficiently as cortical thymic epithelial cells do. Because double-positive thymocytes expressing CD1d select natural killer T (NKT) cells, we investigated whether thymocyte-selected CD4(+) (T-CD4) T cells require the same signaling components as NKT cells. Using bone-marrow chimeras, we found that the signaling molecules SAP, Fyn, and PKCtheta were essential for T-CD4 T cell generation, whereas mutations in the Ly108 receptor, interleukin-15 receptor alpha, or the transcription factor T-bet had a marginal effect. Furthermore, SAP was critical for IL-4 production by T-CD4 T cells, but the PKCtheta deficiency did not alter the ability of T-CD4 T cells to produce cytokines. T-bet was necessary to produce the maximum amount of IFN-gamma for CD4(+) T cells regardless of the selection pathway. Thus, in contrast to epithelial cell-selected CD4(+) T cells, the two distinct lineages of T cells selected by thymocytes--i.e., T-CD4 and NKT cells--both utilize the SAP-Fyn-PKCtheta pathway for their development and function.

Cross‐Talk between CD31 and the Signaling Lymphocytic Activation Molecule–Associated Protein during Interferon‐γ Production againstMycobacterium tuberculosis

Effective host defense against tuberculosis requires Th1 cytokine responses. We studied the regulation of interferon (IFN)- gamma production during tuberculosis by investigating the role of CD31, a receptor that attenuates T cell receptor signals. After antigen stimulation, CD3(+)CD31(+) blood lymphocytes decreased in healthy donors and in tuberculosis patients with robust Th1 responses to Mycobacterium tuberculosis and IFN- gamma was secreted only by CD31(-) T cells. In contrast, in patients with weak Th1 cytokine responses to M. tuberculosis, the level of CD3(+)CD31(+) lymphocytes was increased and IFN- gamma production was low. Furthermore, the inverse relationship between CD31 expression and IFN- gamma production was in contrast to signaling lymphocytic activation molecule (SLAM) expression, an IFN- gamma inducer in tuberculosis. Interestingly, CD31 bound to SLAM-associated protein (SAP), an IFN- gamma inhibitor in tuberculosis, and when CD31 and SAP were coexpressed in lymphocytes, their association inhibited the IFN- gamma response to M. tuberculosis. Thus, CD31, when binding to SAP, interferes with Th1 responses, suggesting that CD31 has a key regulatory role in the signaling pathway(s) leading to the IFN- gamma response to M. tuberculosis.

SLAM‐Associated Protein Solves a Mystery of Autoimmunity

SLAM-associated protein (SAP) is essential for viral protection, lifelong immune memory (vaccination), and lifelong autoantibody production. We discuss how SAP is a key player in the development of autoimmune disease.

Direct and Indirect Interactions of the Cytoplasmic Region of CD244 (2B4) in Mice and Humans with FYN Kinase

Engagement of the receptor CD244 (2B4) by its ligand CD48 has inhibitory and activating potential, and this differs depending on experimental systems in mouse and human. We show that, in both mouse and human upon engagement of its ligand CD48, CD244 can give a negative signal to natural killer cells, implying conservation of function between the two species. The signaling mechanisms used by CD244 in both human and mouse are conserved as shown by quantitative analyses of the direct molecular interactions of the SH2 domains of the adaptors SLAM-associated protein (SAP) and EAT-2 and of FYN kinase with CD244 together with the indirect interactions of the FYN SH2 domain with EAT-2. Functional experiments support the biochemical hierarchy of interactions and show that EAT-2 is not inhibitory per se. The data are consistent with a model in which the mechanism of signal transduction by CD244 is to regulate FYN kinase recruitment and/or activity and the outcome of CD48/CD244 interactions is determined by which other receptors are engaged.

LIMBIC ENCEPHALITIS AS PRESENTATION OF A SAP DEFICIENCY

X-linked lymphoproliferative disease (XLP) is a rare immune cell disorder caused by mutations in the Src homology 2 domain-containing gene 1A (SH2D1A). This gene, located on the X-chromosome, encodes a small cytoplasmic adaptor known as signaling lymphocytic activation molecule (SLAM) associated protein (SAP). SAP is expressed in natural killer cells (NK) and T-cells. It interacts with SLAM and plays a critical role in regulating signaling.1 Clinical manifestations of patients with XLP vary. Most patients die following exposure to Epstein Barr virus (EBV). Boys who survive an EBV infection may develop dysgammaglobulinemia, lymphoma (usually B-cell type), or, less frequently, aplastic anemia, lymphoid granulomatosis, or vasculitis.2–4 Survival into adulthood is rare, although patients treated successfully by bone marrow transplantation (BMT) are recorded.5 Limbic encephalitis is characterized by profound memory impairment, dementia, seizures, usually complex partial, and psychiatric disturbances. On MRI, signal changes are detected on the medial sides of the temporal lobes or in the hippocampi.6,7 We report a patient with limbic encephalitis caused by SAP deficiency. ### Case report. The medical history of the propositus was noteworthy. At age 9 he was …

Regulation of Cellular and Humoral Immune Responses by the SLAM and SAP Families of Molecules

SAP (SLAM-associated protein) was identified in 1998 as an adaptor molecule involved in the intracellular signaling pathways elicited through the cell surface receptor SLAM and as the protein defective in the human immunodeficiency X-linked lymphoproliferative disease (XLP). During the past eight years, it has been established that the SLAM family of cell surface receptors (SLAM, 2B4, NTB-A, Ly9, CD84) and the SAP family of adaptors (SAP, EAT-2, ERT) play critical roles in lymphocyte development, differentiation, and acquisition of effector functions. Studies of these proteins have shown unexpected roles in cytokine production by T cells and myeloid cells, T cell-dependent humoral immune responses, NK cell-mediated cytotoxicity, and NKT cell development. This review highlights recent findings that have improved our understanding of the roles of the SLAM and SAP families of molecules in immune regulation and discusses how perturbations in the signaling pathways involving these proteins can result in different disease states.

Increased proliferation of CD8+ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

Defective signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is responsible for the human X-linked lymphoproliferative syndrome. Defects in T helper 2, natural killer, natural killer T and B cells have been demonstrated in SAP-deficient humans and mice, and increased proliferation of CD8+ T cells has been observed. In the current study, we investigated the properties of CD8+ T cell proliferation and activation-induced cell death (AICD), using OT-I T cell receptor (TCR)-transgenic mice on either wild-type (WT) or SAP-/- background. Interestingly, we found that ovalbumin peptide-activated SAP-/- CD8+ T cells have lower AICD compared to their WT counterparts. Furthermore, the induction of p73, a key mediator of TCR-induced apoptosis through the mitochondrial apoptotic pathway, was significantly reduced at both the mRNA and protein levels in the activated mutant cells. Meanwhile, a reduced level of activated caspase 9 was observed in the mutant cells. We conclude that reduced AICD in activated SAP-/- CD8+ T cells is associated with impaired p73 induction, indicating that the initiation of the mitochondrial apoptotic pathway might be impaired. Our data demonstrate an intrinsic defect in SAP-/- CD8+ T cells and shed light on the increased responsiveness of CD8+ T cells in SAP-/- mice.

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP)) interactions with SLAM family proteins play important roles in immune function. SAP-deficient mice have defective B cell function, including impairment of germinal center formation, production of class-switched Ig, and development of memory B cells. B cells are the major reservoir of latency for both EBV and the homologous murine gammaherpesvirus, gammaherpesvirus 68. There is a strong association between the B cell life cycle and viral latency in that the virus preferentially establishes latency in activated germinal center B cells, which provides access to memory B cells, a major reservoir of long-term latency. In the current studies, we have analyzed the establishment and maintenance of gammaHV68 latency in wild-type and SAP-deficient mice. The results show that, despite SAP-associated defects in germinal center and memory B cell formation, latency was established and maintained in memory B cells at comparable frequencies to wild-type mice, although the paucity of memory B cells translated into a 10-fold reduction in latent load. Furthermore, there were defects in normal latency reservoirs within the germinal center cells and IgD(+)"naive" B cells in SAP-deficient mice, showing a profound effect of the SAP mutation on latency reservoirs.

SAP Regulation of Follicular Helper CD4 T Cell Development and Humoral Immunity Is Independent of SLAM and Fyn Kinase

Mutations in SH2D1A resulting in lack of SLAM-associated protein (SAP) expression cause the human genetic immunodeficiency X-linked lymphoproliferative disease. A severe block in germinal center development and lack of long-term humoral immunity is one of the most prominent phenotypes of SAP(-) mice. We show, in this study, that the germinal center block is due to an essential requirement for SAP expression in Ag-specific CD4 T cells to develop appropriate follicular helper T cell functions. It is unknown what signaling molecules are involved in regulation of SAP-dependent CD4 T cell help functions. SAP binds to the cytoplasmic tail of SLAM, and we show that SLAM is expressed on resting and activated CD4 T cells, as well as germinal center B cells. In addition, SAP can recruit Fyn kinase to SLAM. We have now examined the role(s) of the SLAM-SAP-Fyn signaling axis in in vivo CD4 T cell function and germinal center development. We observed normal germinal center development, long-lived plasma cell development, and Ab responses in SLAM(-/-) mice after a viral infection (lymphocytic choriomeningitis virus). In a separate series of experiments, we show that SAP is absolutely required in CD4 T cells to drive germinal center development, and that requirement does not depend on SAP-Fyn interactions, because CD4 T cells expressing SAP R78A are capable of supporting normal germinal center development. Therefore, a distinct SAP signaling pathway regulates follicular helper CD4 T cell differentiation, separate from the SLAM-SAP-Fyn signaling pathway regulating Th1/Th2 differentiation.

Analysis of natural killer cells isolated from human decidua: evidence that 2B4 (CD244) functions as an inhibitory receptor and blocks NK-cell function

AbstractWhile during the first trimester of pregnancy natural killer (NK) cells represent the most abundant lymphocyte population in the decidua, their actual function at this site is still debated. In this study we analyzed NK cells isolated from decidual tissue for their surface phenotype and functional capability. We show that decidual NK (dNK) cells express normal surface levels of certain activating receptors, including NKp46, NKG2D, and 2B4, as well as of killer cell immunoglobulin-like receptors (KIRs) and CD94/NKG2A inhibitory receptor. In addition, they are characterized by high levels of cytoplasmic granules despite their CD56bright CD16– surface phenotype. Moreover, we provide evidence that in dNK cells, activating NK receptors display normal triggering capability whereas 2B4 functions as an inhibitory receptor. Thus, cross-linking of 2B4 resulted in inhibition of both cytolytic activity and interferon-γ (IFN-γ) production. Clonal analysis revealed that, in the majority of dNK cell clones, the 2B4 inhibitory function is related to the deficient expression of signaling lymphocyte activation molecule (SLAM)–associated protein (SAP) mRNA. Moreover, biochemical analysis revealed low levels of SAP in the dNK polyclonal population. This might suggest that dNK cells, although potentially capable of killing, are inhibited in their function when interacting with cells expressing CD48.

The role of SLAM family receptors in immune cell signalingThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Membrane Proteins in Health and Disease.

The signaling lymphocyte-activating molecule (SLAM) family immunoreceptors are expressed in a wide array of immune cells, including both T and B lymphocytes. By virtue of their ability to transduce tyrosine phosphorylation signals through the so-called ITSM (immunoreceptor tyrosine-based switch motif) sequences, they play an important part in regulating both innate and adaptive immune responses. The critical role of the SLAM immunoreceptors in mediating normal immune reactions was highlighted in recent findings that SAP, a SLAM-associated protein, modulates the activities of various immune cells through interactions with different members of the SLAM family expressed in these cells. Importantly, mutations or deletions of the sap gene in humans result in the X-linked lymphoproliferative syndrome. In this review, we summarize current knowledge and survey the latest developments in signal transduction events triggered by the activation of SLAM family receptors in different cell types.