RESUMEN
The signaling lymphocytic activation molecule (SLAM) receptor family (SLAMF) consists of nine glycoproteins that belong to the CD2 superfamily of immunoglobulin (Ig) domain-containing molecules. SLAMF receptors modulate the differentiation and activation of a wide range of immune cells. Individual SLAMF receptors are expressed on the surface of hematopoietic stem cells, hematopoietic progenitor cells, B cells, T cells, NK cells, NKT cells, monocytes, macrophages, dendritic cells, neutrophils, and platelets. The expression of SLAMF receptors was studied during normal B cell maturation. Several SLAMF receptors were also detected in cancer cell lines of B-lymphoid origin and in pathological B cells from patients with B cell chronic lymphoproliferative disorders (B-CLPD), the most frequent hematological malignancies in adults. This review summarizes current knowledge on the expression of SLAMF receptors and their adaptor proteins SAP and EAT-2 in B-CLPD. Several SLAMF receptors could be regarded as potential diagnostic and differential diagnostic markers, prognostic factors, and targets for the development of novel drugs for patients with B-CLPD.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Trastornos Linfoproliferativos , Adulto , Humanos , Linfocitos B , Plaquetas , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Trastornos Linfoproliferativos/genéticaRESUMEN
Infection of mice by mouse cytomegalovirus (MCMV) triggers activation and expansion of Ly49H+ natural killer (NK) cells, which are virus specific and considered to be "adaptive" or "memory" NK cells. Here, we find that signaling lymphocytic activation molecule family receptors (SFRs), a group of hematopoietic cell-restricted receptors, are essential for the expansion of Ly49H+ NK cells after MCMV infection. This activity is largely mediated by CD48, an SFR broadly expressed on NK cells and displaying augmented expression after MCMV infection. It is also dependent on the CD48 counter-receptor, 2B4, expressed on host macrophages. The 2B4-CD48 axis promotes expansion of Ly49H+ NK cells by repressing their phagocytosis by virus-activated macrophages through inhibition of the pro-phagocytic integrin lymphocyte function-associated antigen-1 (LFA-1) on macrophages. These data identify key roles of macrophages and the 2B4-CD48 pathway in controlling the expansion of adaptive NK cells following MCMV infection. Stimulation of the 2B4-CD48 axis may be helpful in enhancing adaptive NK cell responses for therapeutic purposes.
Asunto(s)
Infecciones por Citomegalovirus , Receptores Inmunológicos , Animales , Ratones , Receptores Inmunológicos/metabolismo , Antígeno CD48/metabolismo , Antígenos CD/metabolismo , Activación de Linfocitos , Células Asesinas Naturales , Receptores de Superficie Celular/metabolismo , Proteínas Portadoras/metabolismo , Macrófagos/metabolismo , FagocitosisRESUMEN
Classical signaling lymphocyte activating molecule (SLAM) family receptors are abundant within many types of immune cells, whereas the nonclassical SLAM family receptors SLAMF8 and SLAMF9, which uniquely lack cytoplasmic signaling motifs, are highly expressed by myeloid cells. Due to the potential redundancy, whether these two receptors regulate macrophage function remains largely unknown. Here, we show that SLAMF8 and SLAMF9 co-regulate macrophage-mediated liver inflammation. To overcome the redundancy, we generated mice that simultaneously lacked SLAMF8 and SLAMF9 using CRISPR-Cas9 technology. Although macrophage differentiation was not altered by the combined deficiency of SLAMF8 and SLAMF9, the loss of these two receptors significantly protected against lipopolysaccharide (LPS)-induced liver injury. SLAMF8 and SLAMF9 double-deficient mice had a prolonged survival rate and less infiltration of inflammatory cells. The depletion of macrophages using clodronate liposomes abolished the effects of SLAMF8 and SLAMF9 deficiencies on LPS-induced liver injury, which demonstrates that these receptors are required for macrophage activation following LPS challenge. Moreover, the deficiency of SLAMF8 and SLAMF9 suppressed the secretion of inflammatory cytokines by downregulating the expression of Toll-like receptor-4 (TLR4), a receptor that specifically binds LPS, which led to decreased mitogen-activated protein kinases (MAPK) signaling activation. Notably, combined injections of truncated extracellular SLAMF8 and SLAMF9 proteins significantly alleviated LPS-induced liver injury. Thus, our findings provide insights into the role of SLAMF8 and SLAMF9 in endotoxin-induced liver injury and suggest that SLAMF8 and SLAMF9 are potential therapeutic targets for acute hepatic injury.
Asunto(s)
Regulación hacia Abajo/genética , Hepatitis/etiología , Hepatitis/inmunología , Lipopolisacáridos/efectos adversos , Sistema de Señalización de MAP Quinasas/genética , Macrófagos/inmunología , Proteínas de la Membrana/deficiencia , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/deficiencia , Receptor Toll-Like 4/metabolismo , Animales , Sistemas CRISPR-Cas , Diferenciación Celular/genética , Citocinas/metabolismo , Hepatitis/metabolismo , Hepatitis/mortalidad , Activación de Macrófagos/genética , Macrófagos/metabolismo , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Células RAW 264.7 , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Tasa de Supervivencia , TransfecciónRESUMEN
The outcome of Multiple Myeloma (MM) patients has dramatically improved, however, most patients will still succumb to their disease. Additional therapeutic options are urgently needed and novel immunotherapies are enormously promising in the therapeutic armamentarium against MM. The first step in the development of any immunotherapy needs to be the identification of an appropriate target structure. In this review we present the current knowledge on surface molecule CD229, a member of the Signaling Lymphocyte Activation (SLAM) family of immune receptors. We believe that based on its characteristics, including (1) strong and homogenous expression on all myeloma cells, (2) expression on myeloma precursors, (3) absence from most normal tissues, (4) a central function in the biology of MM, CD229 (SLAMF3) represents a promising target for anti-MM immunotherapies. The introduction of novel anti-CD229 approaches into the clinic will hopefully lead to more durable responses, or maybe even cures, in MM.
Asunto(s)
Mieloma Múltiple/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Animales , HumanosRESUMEN
CD84 (SLAMF5) is a member of the SLAM family of cell-surface immunoreceptors. Broadly expressed on most immune cell subsets, CD84 functions as a homophilic adhesion molecule, whose signaling can activate or inhibit leukocyte function depending on the cell type and its stage of activation or differentiation. CD84-mediated signaling regulates diverse immunological processes, including T cell cytokine secretion, natural killer cell cytotoxicity, monocyte activation, autophagy, cognate T:B interactions, and B cell tolerance at the germinal center checkpoint. Recently, alterations in CD84 have been related to autoimmune and lymphoproliferative disorders. Specific allelic variations in CD84 are associated with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. In chronic lymphocytic leukemia, CD84 mediates intrinsic and stroma-induced survival of malignant cells. In this review, we describe our current understanding of the structure and function of CD84 and its potential role as a therapeutic target and biomarker in inflammatory autoimmune disorders and cancer.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Biomarcadores/metabolismo , Neoplasias/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Animales , Humanos , Polimorfismo GenéticoRESUMEN
Sjögren's Syndrome (SjS) is a common chronic autoimmune disease characterized by the B cell hyperactivation, lymphocyte infiltration, and tissue damage of exocrine glands. It can also present life-threatening extraglandular manifestations, such as pulmonary and hepatic involvement, renal inflammation and marginal zone (MZ) B cell lymphoma. Several biologic agents have been tested in SjS but none has shown significant efficacy. Here, we report the effects of Ly9 (CD229) antibody targeting, a cell surface molecule that belongs to the SLAM family of immunomodulatory receptors, using NOD.H-2h4 mice as a model of SjS-like disease. Female mice were treated with anti-Ly9 antibody or isotype control at week 24, when all mice present SjS related autoantibodies, salivary gland infiltrates, and marginal zone (MZ) B cell pool enlargement. Antibody injection depleted key lymphocyte subsets involved in SjS pathology such as MZ, B1, and germinal center B cells in spleen and draining lymph nodes without inducing a general immunosuppression. Importantly, mice receiving anti-Ly9 mAb showed a reduced lymphocyte infiltrate within salivary glands. This reduction may be, in part, explained by the down-regulation of L-selectin and alfa4/beta7 integrin induced by the anti-Ly9 antibody. Furthermore, levels of anti-nuclear autoantibodies were reduced after anti-Ly9 treatment. These data indicate that Ly9 is a potential therapeutic target for the treatment of SjS.
Asunto(s)
Linfocitos B/metabolismo , Centro Germinal/patología , Tejido Linfoide/inmunología , Glándulas Salivales/patología , Sialadenitis/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Síndrome de Sjögren/inmunología , Animales , Autoanticuerpos/inmunología , Autoanticuerpos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Movimiento Celular/inmunología , Modelos Animales de Enfermedad , Femenino , Ganglios Linfáticos/patología , Ratones , Ratones Endogámicos NOD , Terapia Molecular Dirigida , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Bazo/patologíaRESUMEN
Wiskott-Aldrich syndrome (WAS) is an immune pathology associated with mutations in WAS protein (WASp) or in WASp interacting protein (WIP). Together with the small GTPase Cdc42 and other effectors, these proteins participate in the remodelling of the actin network downstream of BCR engagement. Here we show that mice lacking the adaptor protein ITSN2, a G-nucleotide exchange factor (GEF) for Cdc42 that also interacts with WASp and WIP, exhibited increased mortality during primary infection, incomplete protection after Flu vaccination, reduced germinal centre formation and impaired antibody responses to vaccination. These defects were found, at least in part, to be intrinsic to the B cell compartment. In vivo, ITSN2 deficient B cells show a reduction in the expression of SLAM, CD84 or ICOSL that correlates with a diminished ability to form long term conjugates with T cells, to proliferate in vivo, and to differentiate into germinal centre cells. In conclusion, our study not only revealed a key role for ITSN2 as an important regulator of adaptive immune-response during vaccination and viral infection but it is also likely to contribute to a better understanding of human immune pathologies.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Linfocitos B/inmunología , Vacunas contra la Influenza/inmunología , Infecciones por Orthomyxoviridae/patología , Orthomyxoviridae/inmunología , Linfocitos T/inmunología , Proteínas Adaptadoras del Transporte Vesicular/deficiencia , Animales , Adhesión Celular , Proliferación Celular , Vacunas contra la Influenza/administración & dosificación , Ratones , Análisis de SupervivenciaRESUMEN
Invariant natural killer T (iNKT) cells develop into three subsets (NKT1, NKT2, and NKT17) expressing a distinct transcription factor profile, which regulates cytokine secretion upon activation. iNKT cell development in the thymus is modulated by signaling lymphocytic activation molecule family (SLAMF) receptors. In contrast to other SLAMF members, Ly9 (SLAMF3) is a non-redundant negative regulator of iNKT cell development. Here, we show that Ly9 influences iNKT cell lineage differentiation. Ly9-deficient mice on a BALB/c background contained a significantly expanded population of thymic NKT2 cells, while NKT1 cells were nearly absent in BALB/c.Ly9-/- thymus. Conversely, the number of peripheral NKT1 cells in BALB/c.Ly9-/- mice was comparable to that in wild-type mice, indicating that the homeostasis of the different iNKT cell subsets may have distinct requirements depending on their tissue localization. Importantly, Ly9 absence also promoted NKT2 cell differentiation in the NKT1-skewed C57BL/6 background. Furthermore, treatment of wild-type mice with an agonistic monoclonal antibody directed against Ly9 impaired IL-4 and IFN-γ production and reduced by half the number of spleen iNKT cells, with a significant decrease in the proportion of NKT2 cells. Thus, anti-Ly9 targeting could represent a novel therapeutic approach to modulate iNKT cell numbers and activation.
Asunto(s)
Diferenciación Celular/inmunología , Activación de Linfocitos/inmunología , Células T Asesinas Naturales/citología , Células T Asesinas Naturales/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Animales , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Bazo/citología , Subgrupos de Linfocitos T/inmunología , Timo/citologíaRESUMEN
Natural killer (NK) cells are important innate immune cells that can directly kill transformed or virus-infected cells. The adoptive transfer of NK cells has been used to treat hematological malignancies; however, the limited sources and quantities of NK cells have restricted their clinical application. Here, we acquired sufficient quantities of functional NK cells from CD34+ cells treated with a cytokine cocktail. Microarray analysis of the cultured cells revealed a two-stage pattern of programmed differentiation during NK cell development. Different transcription factors were enriched during these two stages, suggesting that preparation of progenitors committed to the NK cell lineage occurs in program 1, while NK cell transformation and maturation occur in program 2. Cultured NK cells highly expressed signaling lymphocytic activation molecule (SLAM) family receptors (SFRs), while leukemia cells expressed SFR ligands. The engagement of these SFRs strengthened the cytotoxicity of NK cells toward leukemia cells. These results demonstrate a simple method of obtaining sufficient NK cells for clinical application, and have categorized NK cell differentiation according to commitment and transformation programs. Moreover, the binding between SFRs on NK cells and their ligands on leukemia cells suggests a new basis for NK cell therapy for treatment of leukemia.
RESUMEN
Mutations in SH2D1A gene that encodes SAP (SLAM-associated protein) result in X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency disease defined by exquisite sensitivity to the B-lymphotropic Epstein-Barr virus (EBV) and B cell lymphomas. However, the precise mechanism of how the loss of SAP function contributes to extreme vulnerability to EBV and the development of B cell lymphomas remains unclear. Here, we investigate the hypothesis that SAP is critical for CD8+ T cell immune surveillance of antigen (Ag)-expressing B cells or B lymphoma cells under conditions of defined T cell receptor (TCR) signaling. Sh2d1a-/- CD8+ T cells exhibited greatly diminished proliferation relative to wild type when Ag-presenting-B cells or -B lymphoma cells served as the primary Ag-presenting cell (APC). By contrast, Sh2d1a-/- CD8+ T cells responded equivalently to wild-type CD8+ T cells when B cell-depleted splenocytes, melanoma cells or breast carcinoma cells performed Ag presentation. Through application of signaling lymphocyte activation molecule (SLAM) family receptor blocking antibodies or SLAM family receptor-deficient CD8+ T cells and APCs, we found that CD48 engagement on the B cell surface by 2B4 is crucial for initiating SAP-dependent signaling required for the Ag-driven CD8+ T cell proliferation and differentiation. Altogether, a pivotal role for SAP in promoting the expansion and differentiation of B cell-primed viral-specific naive CD8+ T cells may explain the selective immune deficiency of XLP patients to EBV and B cell lymphomas.
RESUMEN
Whereas the SLAMF-associated protein (SAP) is involved in differentiation of T follicular helper (Tfh) cells and antibody responses, the precise requirements of SLAMF receptors in humoral immune responses are incompletely understood. By analyzing mice with targeted disruptions of the Slamf1, Slamf5, and Slamf6 genes, we found that both T-dependent and T-independent antibody responses were twofold higher compared to those in single knockout mice. These data suggest a suppressive synergy of SLAMF1, SLAMF5, and SLAMF6 in humoral immunity, which contrasts the decreased antibody responses resulting from a defective GC reaction in the absence of the adapter SAP. In adoptive co-transfer assays, both [Slamf1 + 5 + 6] (-/-) B and T cells were capable of inducing enhanced antibody responses, but more pronounced enhancement was observed after adoptive transfer of [Slamf1 + 5 + 6] (-/-) B cells compared to that of [Slamf1 + 5 + 6] (-/-) T cells. In support of [Slamf1 + 5 + 6] (-/-) B cell intrinsic activity, [Slamf1 + 5 + 6] (-/-) mice also mounted significantly higher antibody responses to T-independent type 2 antigen. Furthermore, treatment of mice with anti-SLAMF6 monoclonal antibody results in severe inhibition of the development of Tfh cells and GC B cells, confirming a suppressive effect of SLAMF6. Taken together, these results establish SLAMF1, SLAMF5, and SLAMF6 as important negative regulators of humoral immune response, consistent with the notion that SLAM family receptors have dual functions in immune responses.
RESUMEN
Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP-/- CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP-/- animals. It is however not well understood whether in XLP patients and SAP-/- mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP-/- mice and in Rag-/- mice into which B cells derived from SAP-/- mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP-/- mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP-/- mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP-/- mice, suggests potentially novel therapeutic interventions in subsets of XLP patients.