Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Nature ; 544(7651): 493-497, 2017 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-28424516

RESUMEN

Cancer cells elude anti-tumour immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors. Phagocytosis by macrophages plays a critical role in cancer control. Therapeutic blockade of signal regulatory protein (SIRP)-α, an inhibitory receptor on macrophages, or of its ligand CD47 expressed on tumour cells, improves tumour cell elimination in vitro and in vivo, suggesting that blockade of the SIRPα-CD47 checkpoint could be useful in treating human cancer. However, the pro-phagocytic receptor(s) responsible for tumour cell phagocytosis is(are) largely unknown. Here we find that macrophages are much more efficient at phagocytosis of haematopoietic tumour cells, compared with non-haematopoietic tumour cells, in response to SIRPα-CD47 blockade. Using a mouse lacking the signalling lymphocytic activation molecule (SLAM) family of homotypic haematopoietic cell-specific receptors, we determined that phagocytosis of haematopoietic tumour cells during SIRPα-CD47 blockade was strictly dependent on SLAM family receptors in vitro and in vivo. In both mouse and human cells, this function required a single SLAM family member, SLAMF7 (also known as CRACC, CS1, CD319), expressed on macrophages and tumour cell targets. In contrast to most SLAM receptor functions, SLAMF7-mediated phagocytosis was independent of signalling lymphocyte activation molecule-associated protein (SAP) adaptors. Instead, it depended on the ability of SLAMF7 to interact with integrin Mac-1 (refs 18, 19, 20) and utilize signals involving immunoreceptor tyrosine-based activation motifs. These findings elucidate the mechanism by which macrophages engulf and destroy haematopoietic tumour cells. They also reveal a novel SAP adaptor-independent function for a SLAM receptor. Lastly, they suggest that patients with tumours expressing SLAMF7 are more likely to respond to SIRPα-CD47 blockade therapy.


Asunto(s)
Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/patología , Antígeno de Macrófago-1/metabolismo , Macrófagos/inmunología , Fagocitosis/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Actinas/metabolismo , Animales , Antígenos de Diferenciación/inmunología , Antígenos de Diferenciación/metabolismo , Antígeno CD47/inmunología , Antígeno CD47/metabolismo , Femenino , Neoplasias Hematológicas/tratamiento farmacológico , Humanos , Macrófagos/citología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Noqueados , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/deficiencia
2.
J Clin Immunol ; 41(6): 1291-1302, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33954879

RESUMEN

Mutations in recombinase activating genes 1 and 2 (RAG1/2) result in human severe combined immunodeficiency (SCID). The products of these genes are essential for V(D)J rearrangement of the antigen receptors during lymphocyte development. Mutations resulting in null-recombination activity in RAG1 or RAG2 are associated with the most severe clinical and immunological phenotypes, whereas patients with hypomorphic mutations may develop leaky SCID, including Omenn syndrome (OS). A group of previously unrecognized clinical phenotypes associated with granulomata and/or autoimmunity have been described as a consequence of hypomorphic mutations. Here, we present six patients from unrelated families with missense variants in RAG1 or RAG2. Phenotypes observed in these patients ranged from OS to severe mycobacterial infections and granulomatous disease. Moreover, we report the first evidence of two variants that had not been associated with immunodeficiency. This study represents the first case series of RAG1- or RAG2-deficient patients from Mexico and Latin America.


Asunto(s)
Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Homeodominio/genética , Mutación/genética , Mutación/inmunología , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Adolescente , Niño , Femenino , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Lactante , Linfocitos/inmunología , Masculino , México , Fenotipo
3.
Nat Immunol ; 10(3): 297-305, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19151721

RESUMEN

CRACC is a self-associating member of the signaling lymphocytic activation molecule family that is expressed on cells of the immune system, including natural killer cells and activated T cells. Here we examine the function and mechanism of action of CRACC using several complementary approaches, including the generation of a CRACC-deficient mouse. Our results demonstrate that CRACC positively regulated natural killer cell functions by a mechanism dependent on the adaptor EAT-2 but not the related adaptor SAP. However, in the absence of EAT-2, CRACC potently inhibited natural killer cell function. CRACC was also inhibitory in T cells, which are typically devoid of EAT-2. Thus, CRACC can exert activating or inhibitory influences on cells of the immune system depending on cellular context and the availability of effector proteins.


Asunto(s)
Células Asesinas Naturales/inmunología , Receptores Inmunológicos/metabolismo , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Perfilación de la Expresión Génica , Células Asesinas Naturales/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Receptores Inmunológicos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factores de Transcripción/inmunología
4.
Nat Immunol ; 10(9): 973-80, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19648922

RESUMEN

The adaptors SAP, EAT-2 and ERT are specific to cells of the immune system and belong to the SAP family. All three are expressed in natural killer (NK) cells. Here we examined the global function of the SAP family using mice lacking SAP, EAT-2 and ERT. These adaptors acted together in a mechanism that was essential for the elimination of hematopoietic but not nonhematopoietic cells by NK cells. This function was mediated by many receptors of the SLAM family on NK cells that were engaged by ligands found solely on hematopoietic cells. In the absence of SAP-related adaptors, SLAM receptors lost their activating function and became inhibitory receptors that repressed other activating receptors, such as NKG2D. Hence, the SAP family is essential for the elimination of unwanted hematopoietic cells by NK cells.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Sistema Hematopoyético/citología , Péptidos y Proteínas de Señalización Intracelular/fisiología , Células Asesinas Naturales/fisiología , Animales , Antígenos CD/fisiología , Antígenos Ly/fisiología , Antígeno CD48 , Células CHO , Cricetinae , Cricetulus , Antígenos de Histocompatibilidad Clase I/fisiología , Interferón gamma/biosíntesis , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Subfamilia K de Receptores Similares a Lectina de Células NK/fisiología , Ratas , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Factores de Transcripción/fisiología
5.
J Allergy Clin Immunol ; 146(5): 1165-1179.e11, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32311393

RESUMEN

BACKGROUND: Severe early-onset erythroderma and gut inflammation, with massive tissue infiltration of oligoclonal activated T cells are the hallmark of Omenn syndrome (OS). OBJECTIVE: The impact of altered gut homeostasis in the cutaneous manifestations of OS remains to be clarified. METHODS: We analyzed a cohort of 15 patients with OS and the 129Sv/C57BL/6 knock-in Rag2R229Q/R229Q (Rag2R229Q) mouse model. Homing phenotypes of circulating lymphocytes were analyzed by flow cytometry. Inflammatory cytokines and chemokines were examined in the sera by ELISA and in skin biopsies by immunohistochemistry and in situ RNA hybridization. Experimental colitis was induced in mice by dextran sulfate sodium salt. RESULTS: We show that memory/activated T cells from patients with OS and from the Rag2R229Q mouse model of OS abundantly express the skin homing receptors cutaneous lymphocyte associated antigen and CCR4 (Ccr4), associated with high levels of chemokine C-C motif ligands 17 and 22. Serum levels of LPS are also elevated. A broad Th1/Th2/Th17 inflammatory signature is detected in the periphery and in the skin. Increased Tlr4 expression in the skin of Rag2R229Q mice is associated with enhanced cutaneous inflammation on local and systemic administration of LPS. Likewise, boosting colitis in Rag2R229Q mice results in increased frequency of Ccr4+ splenic T cells and worsening of skin inflammation, as indicated by epidermal thickening, enhanced epithelial cell activation, and dermal infiltration by Th1 effector T cells. CONCLUSIONS: These results support the existence of an interplay between gut and skin that can sustain skin inflammation in OS.


Asunto(s)
Dermatitis/inmunología , Inflamación/inmunología , Intestinos/inmunología , Inmunodeficiencia Combinada Grave/inmunología , Piel/patología , Células TH1/inmunología , Uniones Estrechas/patología , Animales , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Humanos , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Receptores CCR4/metabolismo
8.
Heliyon ; 10(2): e24567, 2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-38312619

RESUMEN

Steatosis is characterized by fat accumulation and insulin resistance (IR) in hepatocytes, which triggers a pro-oxidant, pro-inflammatory environment that may eventually lead to cirrhosis or liver carcinoma. This work was aimed to assess the effect of Sechium edule root hydroalcoholic extract (rSe-HA) (rich in cinnamic and coumaric acid, among other phenolic compounds) on triglyceride esterification, lipid degradation, AMPK expression, and the phosphorylation of insulin receptor in a Ser312 residue, as well as on the redox status, malondialdehyde (MDA) production, and the production of proinflammatory cytokines in an in vitro model of steatosis induced by oleic acid, to help develop a phytomedicine that could reverse this pathology. rSe-HA reduced triglyceride levels in hepatocyte lysates, increased lipolysis by activating AMPK at Thr172, and improved the redox status, as evidenced by the concentration of glycerol and formazan, respectively. It also prevented insulin resistance (IR), as measured by glucose consumption and the phosphorylation of the insulin receptor at Ser312. It also prevented TNFα and IL6 production and decreased the levels of MDA and nitric oxide (ON). Our results indicate that rSe-HA reversed steatosis and controlled the proinflammatory and prooxidant environment in oleic acid-induced dysfunctional HepG2 hepatocytes, supporting its potential use to control this disorder.

9.
Immunol Rev ; 232(1): 229-39, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19909367

RESUMEN

The signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) family of adapters includes SAP, Ewing's sarcoma-associated transcript-2 (EAT-2), and EAT-2-related transducer (ERT). These Src homology-2 (SH2) domain-only molecules play critical roles in immune regulation. The prototype of the SAP family, SAP, is mutated in X-linked lymphoproliferative disease in humans. Moreover, genetically engineered mice lacking one or more SAP family members have defects in multiple immune cell types including T cells, natural killer (NK) cells, NKT cells, and B cells. Accumulating data show that SAP family adapters regulate immunity by influencing the functions of SLAM family receptors, through two distinct but cooperative mechanisms. First, SAP family adapters couple SLAM family receptors to active biochemical signals, which promote immune cell functions. Second, SAP family adapters interfere with the intrinsic ability of SLAM family receptors to trigger inhibitory signals, which could be mediated via molecules such as SH2 domain-containing 5'-inositol phosphatase-1. The latter effect of SAP family adapters does not seem to be because of direct blocking of inhibitory effector binding to SLAM family receptors. Rather, it appears to implicate alternative mechanisms such as functional competition, trans-regulation, or steric hindrance. In the absence of SAP family adapters, the inhibitory signals mediated by SLAM family receptors suppress critical activating receptors, explaining in part the pronounced phenotypes seen in SAP family adapter-deficient humans and mice. Thus, SAP family adapters are molecular switches that regulate immunity as a result of their capacity to control the type of signals and functions emanating from SLAM family receptors.


Asunto(s)
Antígenos CD/metabolismo , Linfocitos/metabolismo , Trastornos Linfoproliferativos/inmunología , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Receptores de Superficie Celular/metabolismo , Factores de Transcripción/metabolismo , Regulación Alostérica , Animales , Antígenos CD/inmunología , Unión Competitiva , Humanos , Linfocitos/inmunología , Linfocitos/patología , Trastornos Linfoproliferativos/genética , Ratones , Ratones Noqueados , Proteína Quinasa 8 Activada por Mitógenos/genética , Proteína Quinasa 8 Activada por Mitógenos/inmunología , Multimerización de Proteína/inmunología , Receptores de Superficie Celular/inmunología , Transducción de Señal/inmunología , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Factores de Transcripción/inmunología , Dominios Homologos src/inmunología
10.
Nutrients ; 15(21)2023 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-37960332

RESUMEN

BACKGROUND: Endothelial dysfunction (ED) is a marker of vascular damage and a precursor of cardiovascular diseases such as hypertension, which involve inflammation and organ damage. Nitric oxide (NO), produced by eNOS, which is induced by pAKT, plays a crucial role in the function of a healthy endothelium. METHODS: A combination of subfractions SF1 and SF3 (C4) of the aqueous fraction from Cucumis sativus (Cs-Aq) was evaluated to control endothelial dysfunction in vivo and on HMEC-1 cells to assess the involvement of pAkt in vitro. C57BL/6J mice were injected daily with angiotensin II (Ang-II) for 10 weeks. Once hypertension was established, either Cs-AqC4 or losartan was orally administered along with Ang-II for a further 10 weeks. Blood pressure (BP) was measured at weeks 0, 5, 10, 15, and 20. In addition, serum creatinine, inflammatory status (in the kidney), tissue damage, and vascular remodeling (in the liver and aorta) were evaluated. Cs-AqC4 was also tested in vitro on HMEC-1 cells stimulated by Ang-II to assess the involvement of Akt phosphorylation. RESULTS: Cs-AqC4 decreased systolic and diastolic BP, reversed vascular remodeling, decreased IL-1ß and TGF-ß, increased IL-10, and decreased kidney and liver damage. In HMEC-1 cells, AKT phosphorylation and NO production were increased. CONCLUSIONS: Cs-AqC4 controlled inflammation and vascular remodeling, alleviating hypertension; it also improved tissue damage associated with ED, probably via Akt activation.


Asunto(s)
Cucumis sativus , Hipertensión , Hormonas Peptídicas , Ratones , Animales , Proteínas Proto-Oncogénicas c-akt , Angiotensina II/farmacología , Remodelación Vascular , Ratones Endogámicos C57BL , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Presión Sanguínea , Inflamación , Componentes Aéreos de las Plantas
12.
Front Immunol ; 13: 803995, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35493522

RESUMEN

In 1975 two independent groups noticed the presence of immune cells with a unique ability to recognize and eliminate transformed hematopoietic cells without any prior sensitization or expansion of specific clones. Since then, NK cells have been the axis of thousands of studies that have resulted until June 2021, in more than 70 000 publications indexed in PubMed. As result of this work, which include approaches in vitro, in vivo, and in natura, it has been possible to appreciate the role played by the NK cells, not only as effectors against specific pathogens, but also as regulators of the immune response. Recent advances have revealed previous unidentified attributes of NK cells including the ability to adapt to new conditions under the context of chronic infections, or their ability to develop some memory-like characteristics. In this review, we will discuss significant findings that have rule our understanding of the NK cell biology, the developing of these findings into new concepts in immunology, and how these conceptual platforms are being used in the design of strategies for cancer immunotherapy.


Asunto(s)
Neoplasias Hematológicas , Neoplasias , Neoplasias Hematológicas/terapia , Humanos , Inmunoterapia/métodos , Células Asesinas Naturales , Neoplasias/terapia
13.
Front Genet ; 13: 971473, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36324500

RESUMEN

A subgroup of congenital disorders of glycosylation (CDGs) includes inherited GPI-anchor deficiencies (IGDs) that affect the biosynthesis of glycosylphosphatidylinositol (GPI) anchors, including the first reaction catalyzed by the X-linked PIGA. Here, we show the first PIGA-CDG case reported in Mexico in a male child with a moderate-to-severe phenotype characterized by neurological and gastrointestinal symptoms, including megacolon. Exome sequencing identified the hemizygous variant PIGA c.145G>A (p.Val49Met), confirmed by Sanger sequencing and characterized as de novo. The pathogenicity of this variant was characterized by flow cytometry and complementation assays in PIGA knockout (KO) cells.

14.
Front Immunol ; 13: 959733, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36238298

RESUMEN

Introduction: The transcription factor Nuclear factor of activated T cells 5 (NFAT5), pivotal in immune regulation and function, can be induced by osmotic stress and tonicity-independent signals. Objective: We aimed to investigate and characterize two unrelated patients with Epstein-Barr virus susceptibility and no known genetic etiology. Methods: After informed consent, we reviewed the electronic charts, extracted genomic DNA, performed whole-exome sequencing, filtered, and prioritized their variants, and confirmed through Sanger sequencing, family segregation analysis, and some functional assays, including lymphoproliferation, cytotoxicity, and characterization of natural killer cells. Results: We describe two cases of pediatric Mexican patients with rare heterozygous missense variants in NFAT5 and EBV susceptibility, a school-age girl with chronic-active infection of the liver and bowel, and a teenage boy who died of hemophagocytic lymphohistiocytosis. Discussion: NFAT5 is an important regulator of the immune response. NFAT5 haploinsufficiency has been described as an immunodeficiency syndrome affecting both innate and adaptive immunity. EBV susceptibility might be another manifestation in the spectrum of this disease.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Linfohistiocitosis Hemofagocítica , Adolescente , Niño , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Femenino , Haploinsuficiencia , Herpesvirus Humano 4 , Humanos , Masculino , Factores de Transcripción/genética
15.
Front Oncol ; 12: 1023510, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36419901

RESUMEN

NK cells have unique attributes to react towards cells undergoing malignant transformation or viral infection. This reactivity is regulated by activating or inhibitory germline encoded receptors. An impaired NK cell function may result from an aberrant expression of such receptors, a condition often seen in patients with hematological cancers. Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer worldwide and NK cells have emerged as crucial targets for developing immunotherapies. However, there are important gaps concerning the phenotype and behavior of NK cells during emergence of ALL. In this study we analyze the phenotype and function of NK cells from peripheral blood in pediatric patients with ALL at diagnosis. Our results showed that NK cells exhibited an altered phenotype highlighted by a significant reduction in the overall expression and percent representation of activating receptors compared to age-matched controls. No significant differences were found for the expression of inhibitory receptors. Moreover, NK cells with a concurrent reduced expression in various activating receptors, was the dominant phenotype among patients. An alteration in the relative frequencies of NK cells expressing NKG2A and CD57 within the mature NK cell pool was also observed. In addition, NK cells from patients displayed a significant reduction in the ability to sustain antibody-dependent cellular cytotoxicity (ADCC). Finally, an aberrant expression of activating receptors is associated with the phenomenon of leukemia during childhood.

16.
PLoS One ; 15(1): e0227314, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31951638

RESUMEN

Acute lymphoblastic leukemia (ALL) is the most common cancer in children around the globe. Mexico City has one of the highest incidence rates of childhood leukemia worldwide with 49.5 cases per million children under the age of 15 which is similar to that reported for Hispanic populations living in the United States. In addition, it has been noted a dismal prognosis in Mexican and Hispanic ALL pediatric population. Although ALL, like cancer in general, has its origins in endogenous, exogenous, and genetic factors, several studies have shown that the immune system also plays a deterministic role in cancer development. Among various elements of the immune system, T lymphocytes and NK cells seem to dominate the immune response against leukemia. The aim of the present study was to perform a phenotypic and functional characterization of NK cells in ALL Mexican children at the moment of diagnosis and before treatment initiation. A case-control study was conducted by the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia (MIGICCL). 41 cases were incident ALL children younger than 17 years old and residents of Mexico City. 14 controls were children without leukemia, matched by age and sex with cases. NK cell function was evaluated by degranulation assays towards K562 cells and SLAM-associated protein (SAP) expression was measured by intracellular staining. All assays were performed using peripheral blood mononuclear cells from controls and patients. The results indicate that NK mediated cytotoxicity, measured by CD107a degranulation assays in response to K562 cells, was reduced in ALL patients compared to controls. Interestingly, an impaired NK cell killing of target cells was not equally distributed among ALL patients. In contrast to patients classified as high-risk, standard-risk patients did not display a significant reduction in NK cell-mediated cytotoxicity. Moreover, patients presenting a leukocyte count ≥ 50,000xmm3 displayed a reduction in NK-cell mediated cytotoxicity and a reduction in SAP expression, indicating a positive correlation between a reduced SAP expression and an impaired NK cell-mediated citotoxicity. In the present study it was observed that unlike patients with standard-risk, NK cells from children presenting high-risk ALL, harbor an impaired cytotoxicity towards K562 at diagnosis. In addition, NK cell function was observed to be compromised in patients with a leukocyte count ≥50,000xmm3, where also it was noticed a decreased expression of SAP compared to patients with a leukocyte count <50,000xmm3. These data indicate NK cell-mediated cytotoxicity is not equally affected in ALL patients, nevertheless a positive correlation between low SAP expression and decreased NK cell-mediated cytotoxicity was observed in ALL patients with a leukocyte count ≥50,000xmm3. Finally, an abnormal NK cell-mediated cytotoxicity may represent a prognostic factor for high-risk acute lymphoblastic leukemia.


Asunto(s)
Células Asesinas Naturales/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria/genética , Linfocitos T Citotóxicos/metabolismo , Adolescente , Estudios de Casos y Controles , Degranulación de la Célula/genética , Degranulación de la Célula/inmunología , Niño , Preescolar , Citotoxicidad Inmunológica/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Células K562 , Células Asesinas Naturales/patología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Proteína 1 de la Membrana Asociada a los Lisosomas/genética , Masculino , México , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Linfocitos T Citotóxicos/patología
17.
J Leukoc Biol ; 105(5): 955-971, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30848847

RESUMEN

The original discovery of NK cells approximately 40 yr ago was based on their unique capability to kill tumor cells without prior sensitization or priming, a process named natural cytotoxicity. Since then, several studies have documented that NK cells can kill hematopoietic and nonhematopoietic cancer cells. NK cells also recognize and kill cells that have undergone viral infections. Besides natural cytotoxicity, NK cells are also major effectors of antibody-dependent cell cytotoxicity (ADCC). Therefore, NK cells are well "armed" to recognize and mount immune responses against "insults" that result from cell transformation and viral infections. Because of these attributes, an essential role of NK cells in tumor surveillance was noted. Indeed, several studies have shown a correlation between impaired NK cell cytotoxicity and a higher risk of developing cancer. This evidence led to the idea that cancer initiation and progress is intimately related to an abnormal or misdirected immune response. Whereas all these ideas remain current, it is also true that NK cells represent a heterogeneous population with different abilities to secrete cytokines and to mediate cytotoxic functions. In addition, recent data has shown that NK cells are prone to suffer epigenetic modifications resulting in the acquisition of previously unrecognized attributes such as memory and long-term survival. Such NK cells, referred as "adaptive" or "memory-like," also display effector functions that are not necessarily equal to those observed in conventional NK cells. Given the new evidence available, it is essential to discuss the conceptual reasoning and misconceptions regarding the role of NK cells in immune surveillance and immunotherapy.


Asunto(s)
Linaje de la Célula/inmunología , Citotoxicidad Inmunológica , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/inmunología , Células Neoplásicas Circulantes/inmunología , Virosis/inmunología , Animales , Citotoxicidad Celular Dependiente de Anticuerpos , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/patología , Modelos Animales de Enfermedad , Humanos , Memoria Inmunológica , Vigilancia Inmunológica , Inmunoterapia/métodos , Células Asesinas Naturales/clasificación , Células Asesinas Naturales/citología , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Ratones , Células Neoplásicas Circulantes/patología , Fenotipo , Virosis/patología , Virosis/virología
18.
Mol Cell Biol ; 35(1): 41-51, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25312647

RESUMEN

Signaling lymphocytic activation molecule F7 (SLAMF7) is a receptor present on immune cells, including natural killer (NK) cells. It is also expressed on multiple myeloma (MM) cells. This led to development of an anti-SLAMF7 antibody, elotuzumab, showing efficacy against MM. SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express or do not express the adaptor EAT-2. Since MM cells lack EAT-2, we elucidated the inhibitory effectors of SLAMF7 in EAT-2-negative NK cells and tested whether these effectors were triggered in MM cells. SLAMF7-mediated inhibition in NK cells lacking EAT-2 was mediated by SH2 domain-containing inositol phosphatase 1 (SHIP-1), which was recruited via tyrosine 261 of SLAMF7. Coupling of SLAMF7 to SHIP-1 required Src kinases, which phosphorylated SLAMF7. Although MM cells lack EAT-2, elotuzumab did not induce inhibitory signals in these cells. This was at least partly due to a lack of CD45, a phosphatase required for Src kinase activation. A defect in SLAMF7 function was also observed in CD45-deficient NK cells. Hence, SLAMF7-triggered inhibition is mediated by a mechanism involving Src kinases, CD45, and SHIP-1 that is defective in MM cells. This defect might explain why elotuzumab eliminates MM cells by an indirect mechanism involving the activation of NK cells.


Asunto(s)
Células Asesinas Naturales/citología , Antígenos Comunes de Leucocito/metabolismo , Mieloma Múltiple/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Receptores Inmunológicos/metabolismo , Familia-src Quinasas/metabolismo , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Células COS , Chlorocebus aethiops , Regulación Neoplásica de la Expresión Génica , Células HeLa , Humanos , Inositol Polifosfato 5-Fosfatasas , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas , Fosforilación , Estructura Terciaria de Proteína , Interferencia de ARN , Transducción de Señal , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Tirosina/química
19.
Trends Immunol ; 27(5): 228-34, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16584920

RESUMEN

The signaling lymphocytic activation molecule (SLAM) and SLAM-associated protein (SAP) families have key roles in normal immunity. They have also been implicated in diseases such as immunodeficiencies and auto-immunity. However, recent findings raise issues requiring examination in future investigations of these molecules. First, Slam-related genes have peculiar features that need to be considered when generating mice lacking SLAM family receptors. Second, there are outstanding questions concerning the functions and mechanisms of action of the SLAM and SAP families. Among these is the possibility that certain properties of these families are not conserved between humans and mice, a controversy about the role of SAP in B cells, gaps in our understanding of the mechanisms by which SAP and Ewing's sarcoma-related transcript (EAT)-2 mediate their signals, and the notion that SLAM family receptors might regulate components of normal immunity in the absence of SAP-related adaptors. We address these issues and discuss the recent progress in this research area.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Antígenos CD/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Superficie Celular/inmunología , Animales , Antígenos CD/genética , Humanos , Modelos Inmunológicos , Receptores de Antígenos de Linfocitos T/clasificación , Receptores de Antígenos de Linfocitos T/genética , Receptores de Superficie Celular/genética , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria
20.
Nat Immunol ; 6(10): 1002-10, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16127454

RESUMEN

EAT-2 is an adaptor expressed in innate immune cells, including natural killer (NK) cells. It is closely related to the adaptor SAP, which regulates signaling lymphocyte activation molecule (SLAM)-related receptors by recruiting the kinase FynT to the receptors. Here we have studied the function of EAT-2 in NK cells by creating mice lacking or overexpressing EAT-2. Like SAP, EAT-2 was associated with the SLAM-related receptor 2B4 in NK cells. However, unlike SAP, EAT-2 was an inhibitor of NK cell function. EAT-2 repressed natural cytotoxicity and interferon-gamma secretion by a mechanism involving tyrosine phosphorylation of its C terminus. We have demonstrated a similar function for the adaptor ERT, a newly identified SAP family member expressed in mouse NK cells. These data identify a previously unknown mechanism of NK cell inhibition. Moreover, they indicate that EAT-2 and SAP have distinct and at times opposing functions in natural immunity.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/fisiología , Células Asesinas Naturales/inmunología , Factores de Transcripción/fisiología , Dominios Homologos src/fisiología , Proteínas Adaptadoras Transductoras de Señales , Secuencia de Aminoácidos , Animales , Animales Modificados Genéticamente , Antígenos CD/genética , Antígenos CD/fisiología , Células CHO , Línea Celular , Cricetinae , Citotoxicidad Inmunológica , Regulación hacia Abajo , Interferón gamma/metabolismo , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/genética , Células Asesinas Naturales/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Datos de Secuencia Molecular , Fosforilación , Receptores Inmunológicos/genética , Receptores Inmunológicos/fisiología , Alineación de Secuencia , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Tirosina , Dominios Homologos src/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA