Mutations that affect the adaptor molecule SLAM-associated protein (SAP) underlie the primary immunodeficiency disease X-linked lymphoproliferative syndrome. SAP is required for mediating signals from members of the signalling lymphocytic activation molecule (SLAM) family of immunomodulatory receptors. Recent data have highlighted a role for SAP in the development of innate-like T-cell lineages, including natural killer T cells, and in the regulation of the interactions between B cells and T cells that are required for germinal-centre formation and long-term humoral immunity. These data have revealed that SLAM family members and SAP have crucial roles in regulating lymphocyte interactions and adhesion, which are required for the normal development, homeostasis and function of the immune system.
"Slamf1 encodes CD150, a lymphocyte signaling and adhesion molecule (50) that is expressed in B cells and T cells and at very low levels in myeloid cells (see www.immgen.org). Our RNAseq analysis of activated B cells indicated that Slamf1 was expressed at abnormally low levels in Oct2 KO B compared to controls (Figure 4A). "
[Show abstract][Hide abstract] ABSTRACT: The Oct2 protein, encoded by the Pou2f2 gene, was originally predicted to act as a DNA binding transcriptional activator of immunoglobulin (Ig) in B lineage cells. This prediction flowed from the earlier observation that an 8-bp sequence, the "octamer motif," was a highly conserved component of most Ig gene promoters and enhancers, and evidence from over-expression and reporter assays confirmed Oct2-mediated, octamer-dependent gene expression. Complexity was added to the story when Oct1, an independently encoded protein, ubiquitously expressed from the Pou2f1 gene, was characterized and found to bind to the octamer motif with almost identical specificity, and later, when the co-activator Obf1 (OCA-B, Bob.1), encoded by the Pou2af1 gene, was cloned. Obf1 joins Oct2 (and Oct1) on the DNA of a subset of octamer motifs to enhance their transactivation strength. While these proteins variously carried the mantle of determinants of Ig gene expression in B cells for many years, such a role has not been borne out for them by characterization of mice lacking functional copies of the genes, either as single or as compound mutants. Instead, we and others have shown that Oct2 and Obf1 are required for B cells to mature fully in vivo, for B cells to respond to the T cell cytokines IL5 and IL4, and for B cells to produce IL6 normally during a T cell dependent immune response. We show here that Oct2 affects Syk gene expression, thus influencing B cell receptor signaling, and that Oct2 loss blocks Slamf1 expression in vivo as a result of incomplete B cell maturation. Upon IL4 signaling, Stat6 up-regulates Obf1, indirectly via Xbp1, to enable plasma cell differentiation. Thus, Oct2 and Obf1 enable B cells to respond normally to antigen receptor signals, to express surface receptors that mediate physical interaction with T cells, or to produce and respond to cytokines that are critical drivers of B cell and T cell differentiation during a humoral immune response.
Frontiers in Immunology 03/2014; 5:108. DOI:10.3389/fimmu.2014.00108
"They belong to the family of signaling lymphocyte activation molecule (SLAM)-related receptors (SRR) (Claus et al., 2008). More and more evidence is emerging demonstrating that this family of Ig-like receptors plays a role in fine-tuning of immune responses, e.g., in germinal center formation or development of innate-like T cells (Schwartzberg et al., 2009). All SRR are homophilic with the exception of 2B4 that binds to CD48, another Ig-like protein with broad expression in the hematopoietic system (Claus et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: 2B4 (CD244) and NK-T-B-antigen (NTB-A, CD352) are activating receptors on human natural killer (NK) cells and belong to the family of signaling lymphocyte activation molecule (SLAM)-related receptors (SRR). Engagement of these receptors leads to phosphorylation of their cytoplasmic tails and recruitment of the adapter proteins SLAM-associated protein (SAP) and Ewing's sarcoma-activated transcript-2 (EAT-2). X-linked lymphoproliferative syndrome (XLP) is a severe immunodeficiency that results from mutations in the SAP gene. 2B4 and NTB-A-mediated cytotoxicity are abrogated in XLP NK cells. To elucidate the molecular basis for this defect we analyzed early signaling events in SAP knockdown cells. Similar to XLP NK cells, knockdown of SAP in primary human NK cells leads to a reduction of 2B4 and NTB-A-mediated cytotoxicity. We found that early signaling events such as raft recruitment and receptor phosphorylation are not affected by the absence of SAP, indicating the defect in the absence of SAP is downstream of these events. In addition, knockdown of EAT-2 does not impair 2B4 or NTB-A-mediated cytotoxicity. Surprisingly, EAT-2 recruitment to both receptors is abrogated in the absence of SAP, revealing a novel cooperativity between these adapters.
Frontiers in Immunology 01/2013; 4:3. DOI:10.3389/fimmu.2013.00003
"SLAMF-associated proteins are important immunomodulatory receptors with roles in cytotoxicity, humoral immunity, autoimmunity, cell survival, lymphocyte development, and cell adhesion . Whereas SLAMF1, 3 and 7 are strongly upregulated by BCR crosslinking, SLAMF6 is inhibited. "
[Show abstract][Hide abstract] ABSTRACT: Background
Aggressive Non-Hodgkin lymphomas (NHL) are a group of lymphomas derived from germinal centre B cells which display a heterogeneous pattern of oncogenic pathway activation. We postulate that specific immune response associated signalling, affecting gene transcription networks, may be associated with the activation of different oncogenic pathways in aggressive Non-Hodgkin lymphomas (NHL).
The B cell receptor (BCR), CD40, B-cell activating factor (BAFF)-receptors and Interleukin (IL) 21 receptor and Toll like receptor 4 (TLR4) were stimulated in human transformed germinal centre B cells by treatment with anti IgM F(ab)2-fragments, CD40L, BAFF, IL21 and LPS respectively. The changes in gene expression following the activation of Jak/STAT, NF-кB, MAPK, Ca2+ and PI3K signalling triggered by these stimuli was assessed using microarray analysis. The expression of top 100 genes which had a change in gene expression following stimulation was investigated in gene expression profiles of patients with Aggressive non-Hodgkin Lymphoma (NHL).
αIgM stimulation led to the largest number of changes in gene expression, affecting overall 6596 genes. While CD40L stimulation changed the expression of 1194 genes and IL21 stimulation affected 902 genes, only 283 and 129 genes were modulated by lipopolysaccharide or BAFF receptor stimulation, respectively. Interestingly, genes associated with a Burkitt-like phenotype, such as MYC, BCL6 or LEF1, were affected by αIgM. Unique and shared gene expression was delineated. NHL-patients were sorted according to their similarity in the expression of TOP100 affected genes to stimulated transformed germinal centre B cells The αIgM gene module discriminated individual DLBCL in a similar manner to CD40L or IL21 gene modules. DLBCLs with low module activation often carry chromosomal MYC aberrations. DLBCLs with high module activation show strong expression of genes involved in cell-cell communication, immune responses or negative feedback loops. Using chemical inhibitors for selected kinases we show that mitogen activated protein kinase- and phosphoinositide 3 kinase-signalling are dominantly involved in regulating genes included in the αIgM gene module.
We provide an in vitro model system to investigate pathway activation in lymphomas. We defined the extent to which different immune response associated pathways are responsible for differences in gene expression which distinguish individual DLBCL cases. Our results support the view that tonic or constitutively active MAPK/ERK pathways are an important part of oncogenic signalling in NHL. The experimental model can now be applied to study the therapeutic potential of deregulated oncogenic pathways and to develop individual treatment strategies for lymphoma patients.
Cell Communication and Signaling 12/2012; 10(1):43. DOI:10.1186/1478-811X-10-43 · 3.38 Impact Factor
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