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1.
Nat Immunol ; 18(2): 184-195, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27992400

RESUMEN

Invariant natural killer T cells (iNKT cells) are innate-like lymphocytes that protect against infection, autoimmune disease and cancer. However, little is known about the epigenetic regulation of iNKT cell development. Here we found that the H3K27me3 histone demethylase UTX was an essential cell-intrinsic factor that controlled an iNKT-cell lineage-specific gene-expression program and epigenetic landscape in a demethylase-activity-dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT cell signature genes due to a decrease in activation-associated H3K4me3 marks and an increase in repressive H3K27me3 marks within the promoters occupied by UTX. We found that JunB regulated iNKT cell development and that the expression of genes that were targets of both JunB and the iNKT cell master transcription factor PLZF was UTX dependent. We identified iNKT cell super-enhancers and demonstrated that UTX-mediated regulation of super-enhancer accessibility was a key mechanism for commitment to the iNKT cell lineage. Our findings reveal how UTX regulates the development of iNKT cells through multiple epigenetic mechanisms.


Asunto(s)
Diferenciación Celular , Epigénesis Genética , Regulación de la Expresión Génica , Histona Demetilasas/metabolismo , Células T Asesinas Naturales/fisiología , Animales , Linaje de la Célula , Células Cultivadas , Elementos de Facilitación Genéticos/genética , Histona Demetilasas/genética , Inmunidad Innata/genética , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos , Regiones Promotoras Genéticas/genética , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
2.
Nat Immunol ; 17(10): 1159-66, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27548435

RESUMEN

CD1a is a lipid-presenting molecule that is abundantly expressed on Langerhans cells. However, the in vivo role of CD1a has remained unclear, principally because CD1a is lacking in mice. Through the use of mice with transgenic expression of CD1a, we found that the plant-derived lipid urushiol triggered CD1a-dependent skin inflammation driven by CD4(+) helper T cells that produced the cytokines IL-17 and IL-22 (TH17 cells). Human subjects with poison-ivy dermatitis had a similar cytokine signature following CD1a-mediated recognition of urushiol. Among various urushiol congeners, we identified diunsaturated pentadecylcatechol (C15:2) as the dominant antigen for CD1a-restricted T cells. We determined the crystal structure of the CD1a-urushiol (C15:2) complex, demonstrating the molecular basis of urushiol interaction with the antigen-binding cleft of CD1a. In a mouse model and in patients with psoriasis, CD1a amplified inflammatory responses that were mediated by TH17 cells that reacted to self lipid antigens. Treatment with blocking antibodies to CD1a alleviated skin inflammation. Thus, we propose CD1a as a potential therapeutic target in inflammatory skin diseases.


Asunto(s)
Antígenos CD1/metabolismo , Autoantígenos/metabolismo , Catecoles/metabolismo , Dermatitis por Toxicodendron/inmunología , Células de Langerhans/inmunología , Psoriasis/inmunología , Células Th17/inmunología , Animales , Anticuerpos Bloqueadores/administración & dosificación , Antígenos CD1/genética , Antígenos CD1/inmunología , Catecoles/química , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Humanos , Interleucina-17/metabolismo , Interleucinas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Conformación Proteica , Toxicodendron/inmunología , Interleucina-22
3.
J Hepatol ; 79(5): 1214-1225, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37348791

RESUMEN

BACKGROUND & AIMS: Glycoprotein A repetitions predominant (GARP) is a membrane protein that functions as a latent TGF-ß docking molecule. While the immune regulatory properties of GARP on blood cells have been studied, the function of GARP on tissue stromal cells remains unclear. Here, we investigate the role of GARP expressed on hepatic stellate cells (HSCs) in the development of liver fibrosis. METHODS: The function of GARP on HSCs was explored in toxin-induced and metabolic liver fibrosis models, using conditional GARP-deficient mice or a newly generated inducible system for HSC-specific gene ablation. Primary mouse and human HSCs were isolated to evaluate the contribution of GARP to the activation of latent TGF-ß. Moreover, cell contraction of HSCs in the context of TGF-ß activation was tested in a GARP-dependent fashion. RESULTS: Mice lacking GARP in HSCs were protected from developing liver fibrosis. Therapeutically deleting GARP on HSCs alleviated the fibrotic process in established disease. Furthermore, natural killer T cells exacerbated hepatic fibrosis by inducing GARP expression on HSCs through IL-4 production. Mechanistically, GARP facilitated fibrogenesis by activating TGF-ß and enhancing endothelin-1-mediated HSC contraction. Functional GARP was expressed on human HSCs and significantly upregulated in the livers of patients with fibrosis. Lastly, deletion of GARP on HSCs did not augment inflammation or liver damage. CONCLUSIONS: GARP expressed on HSCs drives the development of liver fibrosis via cell contraction-mediated activation of latent TGF-ß. Considering that systemic blockade of TGF-ß has major side effects, we highlight a therapeutic niche provided by GARP and surface-mediated TGF-ß activation. Thus, our findings suggest an important role of GARP on HSCs as a promising target for the treatment of liver fibrosis. IMPACT AND IMPLICATIONS: Liver fibrosis represents a substantial and increasing public health burden globally, for which specific treatments are not available. Glycoprotein A repetitions predominant (GARP) is a membrane protein that functions as a latent TGF-ß docking molecule. Here, we show that GARP expressed on hepatic stellate cells drives the development of liver fibrosis. Our findings suggest GARP as a novel target for the treatment of fibrotic disease.

4.
Immunity ; 41(4): 505-6, 2014 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-25367563

RESUMEN

The most powerful iNKT cell antigen is α-galactosylceramide (α-GalCer), derived from the marine sponge. However, α-anomeric glycolipids are thought to be absent in mammals. In this issue of Immunity, Kain et al., (2014) demonstrate the presence of mammalian α-linked glycosylceramides, such as α-GalCer.


Asunto(s)
Linfocitos B/enzimología , Glucosilceramidas/biosíntesis , Células T Asesinas Naturales/inmunología , Linfocitos T/enzimología , Animales , Humanos
5.
Immunity ; 33(2): 216-28, 2010 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-20727792

RESUMEN

Natural Killer T (NKT) cells are lipid-reactive, CD1d-restricted T lymphocytes important in infection, cancer, and autoimmunity. In addition to foreign antigens, NKT cells react with endogenous self lipids. However, in the face of stimulating self antigen, it remains unclear how overstimulation of NKT cells is avoided. We hypothesized that constantly degraded endogenous antigen only accumulates upon inhibition of alpha-galactosidase A (alpha-Gal-A) in lysosomes. Here, we show that alpha-Gal-A deficiency caused vigorous activation of NKT cells. Moreover, microbes induced inhibition of alpha-Gal-A activity in antigen-presenting cells. This temporary enzyme block depended on Toll-like receptor (TLR) signaling and ultimately triggered lysosomal lipid accumulation. Thus, we present TLR-dependent negative regulation of alpha-Gal-A as a mechanistic link between pathogen recognition and self lipid antigen induction for NKT cells.


Asunto(s)
Autoantígenos/inmunología , Lípidos/inmunología , Lisosomas/inmunología , Células T Asesinas Naturales/inmunología , alfa-Galactosidasa/inmunología , Animales , Presentación de Antígeno , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/inmunología , Homeostasis , Activación de Linfocitos , Lisosomas/enzimología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/deficiencia , Factor 88 de Diferenciación Mieloide/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , Células T Asesinas Naturales/enzimología , Transducción de Señal , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismo , alfa-Galactosidasa/metabolismo
6.
Science ; 383(6679): 190-200, 2024 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-38207022

RESUMEN

Tumors develop strategies to evade immunity by suppressing antigen presentation. In this work, we show that prosaposin (pSAP) drives CD8 T cell-mediated tumor immunity and that its hyperglycosylation in tumor dendritic cells (DCs) leads to cancer immune escape. We found that lysosomal pSAP and its single-saposin cognates mediated disintegration of tumor cell-derived apoptotic bodies to facilitate presentation of membrane-associated antigen and T cell activation. In the tumor microenvironment, transforming growth factor-ß (TGF-ß) induced hyperglycosylation of pSAP and its subsequent secretion, which ultimately caused depletion of lysosomal saposins. pSAP hyperglycosylation was also observed in tumor-associated DCs from melanoma patients, and reconstitution with pSAP rescued activation of tumor-infiltrating T cells. Targeting DCs with recombinant pSAP triggered tumor protection and enhanced immune checkpoint therapy. Our studies demonstrate a critical function of pSAP in tumor immunity and may support its role in immunotherapy.


Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Saposinas , Escape del Tumor , Humanos , Células Dendríticas/inmunología , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Saposinas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Microambiente Tumoral , Glicosilación , Inmunoterapia , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Presentación de Antígeno , Linfocitos T CD8-positivos/inmunología
7.
Science ; 383(6684): eadg0564, 2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38359115

RESUMEN

Influenza viruses escape immunity owing to rapid antigenic evolution, which requires vaccination strategies that allow for broadly protective antibody responses. We found that the lipid globotriaosylceramide (Gb3) expressed on germinal center (GC) B cells is essential for the production of high-affinity antibodies. Mechanistically, Gb3 bound and disengaged CD19 from its chaperone CD81, permitting CD19 to translocate to the B cell receptor complex to trigger signaling. Moreover, Gb3 regulated major histocompatibility complex class II expression to increase diversity of T follicular helper and GC B cells reactive with subdominant epitopes. In influenza infection, elevating Gb3, either endogenously or exogenously, promoted broadly reactive antibody responses and cross-protection. These data demonstrate that Gb3 determines the affinity and breadth of B cell immunity and has potential as a vaccine adjuvant.


Asunto(s)
Anticuerpos Antivirales , Linfocitos B , Centro Germinal , Infecciones por Orthomyxoviridae , Orthomyxoviridae , Trihexosilceramidas , Formación de Anticuerpos , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Centro Germinal/efectos de los fármacos , Centro Germinal/inmunología , Trihexosilceramidas/metabolismo , Trihexosilceramidas/farmacología , Animales , Ratones , Ratones Noqueados , Humanos , Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/inmunología , Anticuerpos Antivirales/biosíntesis , Anticuerpos Antivirales/inmunología
8.
Nat Med ; 12(9): 1030-8, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16951684

RESUMEN

Helicobacter pylori infection causes gastric pathology such as ulcer and carcinoma. Because H. pylori is auxotrophic for cholesterol, we have explored the assimilation of cholesterol by H. pylori in infection. Here we show that H. pylori follows a cholesterol gradient and extracts the lipid from plasma membranes of epithelial cells for subsequent glucosylation. Excessive cholesterol promotes phagocytosis of H. pylori by antigen-presenting cells, such as macrophages and dendritic cells, and enhances antigen-specific T cell responses. A cholesterol-rich diet during bacterial challenge leads to T cell-dependent reduction of the H. pylori burden in the stomach. Intrinsic alpha-glucosylation of cholesterol abrogates phagocytosis of H. pylori and subsequent T cell activation. We identify the gene hp0421 as encoding the enzyme cholesterol-alpha-glucosyltransferase responsible for cholesterol glucosylation. Generation of knockout mutants lacking hp0421 corroborates the importance of cholesteryl glucosides for escaping phagocytosis, T cell activation and bacterial clearance in vivo. Thus, we propose a mechanism regulating the host-pathogen interaction whereby glucosylation of a lipid tips the scales towards immune evasion or response.


Asunto(s)
Colesterol/metabolismo , Glucosa/metabolismo , Glucosiltransferasas/metabolismo , Helicobacter pylori/metabolismo , Animales , Membrana Celular/metabolismo , Colesterol/farmacología , Citocinas/biosíntesis , Células Epiteliales/metabolismo , Mucosa Gástrica/microbiología , Glicosilación , Infecciones por Helicobacter/enzimología , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Humanos , Inmunidad Innata , Macrófagos/fisiología , Microdominios de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Fagocitosis/efectos de los fármacos , Neoplasias Gástricas , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/fisiología , Células Tumorales Cultivadas
9.
bioRxiv ; 2023 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-37398287

RESUMEN

Tumors develop strategies to evade immunity by suppressing antigen presentation. Here, we show that prosaposin drives CD8 T cell-mediated tumor immunity and that its hyperglycosylation in tumor DCs leads to cancer immune escape. We found that lysosomal prosaposin and its single saposin cognates mediated disintegration of tumor cell-derived apoptotic bodies to facilitate presentation of membrane-associated antigen and T cell activation. In the tumor microenvironment, TGF-ß induced hyperglycosylation of prosaposin and its subsequent secretion, which ultimately caused depletion of lysosomal saposins. In melanoma patients, we found similar prosaposin hyperglycosylation in tumor-associated DCs, and reconstitution with prosaposin rescued activation of tumor-infiltrating T cells. Targeting tumor DCs with recombinant prosaposin triggered cancer protection and enhanced immune checkpoint therapy. Our studies demonstrate a critical function of prosaposin in tumor immunity and escape and introduce a novel principle of prosaposin-based cancer immunotherapy. One Sentence Summary: Prosaposin facilitates antigen cross-presentation and tumor immunity and its hyperglycosylation leads to immune evasion.

10.
bioRxiv ; 2023 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-37790573

RESUMEN

Influenza viruses escape immunity due to rapid antigenic evolution, which requires vaccination strategies that allow for broadly protective antibody responses. Here, we demonstrate that the lipid globotriaosylceramide (Gb3) expressed on germinal center (GC) B cells is essential for the production of high-affinity antibodies. Mechanistically, Gb3 binds and disengages CD19 from its chaperone CD81 for subsequent translocation to the B cell receptor (BCR) complex to trigger signaling. Abundance of Gb3 amplifies the PI3-kinase/Akt/Foxo1 pathway to drive affinity maturation. Moreover, this lipid regulates MHC-II expression to increase diversity of T follicular helper (Tfh) and GC B cells reactive with subdominant epitopes. In influenza infection, Gb3 promotes broadly reactive antibody responses and cross-protection. Thus, we show that Gb3 determines affinity as well as breadth in B cell immunity and propose this lipid as novel vaccine adjuvant against viral infection. One Sentence Summary: Gb3 abundance on GC B cells selects antibodies with high affinity and broad epitope reactivities, which are cross-protective against heterologous influenza infection.

11.
Curr Opin Immunol ; 20(1): 68-74, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18068343

RESUMEN

Stellate cells are star-shaped cells located in the liver and mediate a multitude of primarily non-immunological functions. They play a pivotal role in the metabolism of vitamin A and store 80% of total body retinol. Upon activation, stellate cells differentiate to myofibroblasts for production of extracellular matrix, leading to liver fibrosis. Moreover, activated stellate cells regulate liver blood flow through vasoconstriction implicated in portal hypertension. Earlier work demonstrated stellate cell derived secretion of chemokines and cytokines such as transforming growth factor beta (TGF-beta), suggesting an association with immunological processes. Indeed, recent evidence indicated that hepatic stellate cells perform potent APC function for stimulation of NKT cells as well as CD8 and CD4 T cells. Additionally, stellate cell mediated antigen presentation induced protective immunity against bacterial infection. Current experiments reveal that the presenting ability of stellate cells is the key to antigen-dependent T cell instruction by vitamin A derived retinoic acid. Finally, future studies will show whether in the firmament of immunology stellate cells will represent fixed or falling stars.


Asunto(s)
Presentación de Antígeno , Células Presentadoras de Antígenos/inmunología , Hígado/inmunología , Animales , Humanos , Hígado/citología , Hígado/fisiología
12.
PLoS Pathog ; 5(5): e1000434, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19436711

RESUMEN

The innate immune response is supposed to play an essential role in the control of amebic liver abscess (ALA), a severe form of invasive amoebiasis due to infection with the protozoan parasite Entamoeba histolytica. In a mouse model for the disease, we previously demonstrated that Jalpha18(-/-) mice, lacking invariant natural killer T (iNKT) cells, suffer from more severe abscess development. Here we show that the specific activation of iNKT cells using alpha-galactosylceramide (alpha-GalCer) induces a significant reduction in the sizes of ALA lesions, whereas CD1d(-/-) mice develop more severe abscesses. We identified a lipopeptidophosphoglycan from E. histolytica membranes (EhLPPG) as a possible natural NKT cell ligand and show that the purified phosphoinositol (PI) moiety of this molecule induces protective IFN-gamma but not IL-4 production in NKT cells. The main component of EhLPPG responsible for NKT cell activation is a diacylated PI, (1-O-[(28:0)-lyso-glycero-3-phosphatidyl-]2-O-(C16:0)-Ins). IFN-gamma production by NKT cells requires the presence of CD1d and simultaneously TLR receptor signalling through MyD88 and secretion of IL-12. Similar to alpha-GalCer application, EhLPPG treatment significantly reduces the severity of ALA in ameba-infected mice. Our results suggest that EhLPPG is an amebic molecule that is important for the limitation of ALA development and may explain why the majority of E. histolytica-infected individuals do not develop amebic liver abscess.


Asunto(s)
Entamoeba histolytica/inmunología , Entamoeba histolytica/patogenicidad , Absceso Hepático Amebiano/inmunología , Células T Asesinas Naturales/inmunología , Peptidoglicano/inmunología , Fosfolípidos/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Antígenos CD1d/genética , Antígenos de Protozoos/inmunología , Antígenos de Superficie/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Galactosilceramidas/inmunología , Interferón gamma/inmunología , Absceso Hepático Amebiano/parasitología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Fosfatidilinositoles/química , Transducción de Señal/inmunología , Trofozoítos/inmunología
13.
Nat Med ; 9(8): 1039-46, 2003 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12872166

RESUMEN

Protective immunity against Mycobacterium tuberculosis involves major histocompatibility complex class I (MHC-I)- and CD1-restricted CD8 T cells, but the mechanisms underlying antigen delivery to antigen-presenting molecules remain enigmatic. Macrophages, the primary host cells for mycobacteria, are CD1-negative. Here we show that M. tuberculosis phagosomes are secluded from the cytosolic MHC-I processing pathway and that mycobacteria-infected cells lose their antigen-presenting capacity. We also show that mycobacteria induce apoptosis in macrophages, causing the release of apoptotic vesicles that carry mycobacterial antigens to uninfected antigen-presenting cells (APCs). Inhibition of apoptosis reduced transfer of antigens to bystander cells and activation of CD8 T cells. Uninfected dendritic cells, which engulfed extracellular vesicles, were indispensable for subsequent cross-presentation of antigens, through MHC-I and CD1b, to T cells from mycobacteria-sensitized donors. This new 'detour' pathway for presentation of antigens from a phagosome-contained pathogen shows the functional significance of infection-induced apoptosis in the activation of CD8 T cells specific for both protein and glycolipid antigens in tuberculosis.


Asunto(s)
Presentación de Antígeno , Antígenos CD1/inmunología , Apoptosis/fisiología , Linfocitos T CD8-positivos/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Tuberculosis/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Células Presentadoras de Antígenos/ultraestructura , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/metabolismo , Genes MHC Clase I , Humanos , Listeria monocytogenes/citología , Listeria monocytogenes/metabolismo , Activación de Linfocitos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Mycobacterium tuberculosis/citología , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/metabolismo , Fagosomas/metabolismo
14.
J Virol ; 82(9): 4308-19, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18287231

RESUMEN

The betaherpesvirus human cytomegalovirus (HCMV) encodes several molecules that block antigen presentation by the major histocompatibility complex (MHC) proteins. Humans also possess one other family of antigen-presenting molecules, the CD1 family; however, the effect of HCMV on CD1 expression is unknown. The majority of CD1 molecules are classified on the basis of homology as group 1 CD1 and are present almost exclusively on professional antigen-presenting cells such as dendritic cells, which are a major target for HCMV infection and latency. We have determined that HCMV encodes multiple blocking strategies targeting group 1 CD1 molecules. CD1 transcription is strongly inhibited by the HCMV interleukin-10 homologue cmvIL-10. HCMV also blocks CD1 antigen presentation posttranscriptionally by the inhibition of CD1 localization to the cell surface. This function is not performed by a known HCMV MHC class I-blocking molecule and is substantially stronger than the blockage induced by herpes simplex virus type 1. Antigen presentation by CD1 is important for the development of the antiviral immune response and the generation of mature antigen-presenting cells. HCMV present in antigen-presenting cells thus blunts the immune response by the blockage of CD1 molecules.


Asunto(s)
Presentación de Antígeno/inmunología , Antígenos CD1/inmunología , Citomegalovirus/inmunología , Antígenos CD1/genética , Antígenos CD1/metabolismo , Línea Celular , Células Cultivadas , Citomegalovirus/fisiología , Regulación de la Expresión Génica/inmunología , Humanos , Inmunidad , Transporte de Proteínas , Transcripción Genética/inmunología
15.
Nat Commun ; 10(1): 617, 2019 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-30728354

RESUMEN

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for blood and immune diseases with potential for many settings beyond current standard-of-care. Broad HSCT application is currently precluded largely due to morbidity and mortality associated with genotoxic irradiation or chemotherapy conditioning. Here we show that a single dose of a CD117-antibody-drug-conjugate (CD117-ADC) to saporin leads to > 99% depletion of host HSCs, enabling rapid and efficient donor hematopoietic cell engraftment. Importantly, CD117-ADC selectively targets hematopoietic stem cells yet does not cause clinically significant side-effects. Blood counts and immune cell function are preserved following CD117-ADC treatment, with effective responses by recipients to both viral and fungal challenges. These results suggest that CD117-ADC-mediated HSCT pre-treatment could serve as a non-myeloablative conditioning strategy for the treatment of a wide range of non-malignant and malignant diseases, and might be especially suited to gene therapy and gene editing settings in which preservation of immunity is desired.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/efectos de los fármacos , Inmunoconjugados/farmacología , Proteínas Proto-Oncogénicas c-kit/inmunología , Animales , Médula Ósea/efectos de los fármacos , Trasplante de Médula Ósea , Candida albicans/patogenicidad , Muerte Celular , Línea Celular , Femenino , Terapia Genética , Humanos , Inmunoconjugados/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Neoplasias , Donantes de Tejidos
16.
J Exp Med ; 213(12): 2759-2772, 2016 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-27810927

RESUMEN

In chronic infection, T cells become hyporesponsive to antigenic stimulation to prevent immunopathology. Here, we show that TMEM16F is required to curb excessive T cell responses in chronic infection with virus. TMEM16F-deficient T cells are hyperactivated during the early phase of infection, exhibiting increased proliferation and cytokine production. Interestingly, this overactivation ultimately leads to severe T cell exhaustion and the inability of the host to control viral burden. Mechanistically, we identify TMEM16F as the dominant lipid scramblase in T lymphocytes that transports phospholipids across membranes. TMEM16F is located in late endosomes, where it facilitates the generation of multivesicular bodies for TCR degradation and signal termination. Consequently, TMEM16F deficiency results in sustained signaling and augmented T cell activation. Our results demonstrate that scramblase restricts TCR responses to avoid overactivation, ensuring a well-balanced immune response in chronic infectious disease.


Asunto(s)
Proteínas de Transferencia de Fosfolípidos/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Linfocitos T/inmunología , Actinas/metabolismo , Animales , Anoctaminas , Enfermedad Crónica , Endocitosis , Endosomas/metabolismo , Silenciador del Gen , Humanos , Sinapsis Inmunológicas/metabolismo , Células Jurkat , Activación de Linfocitos/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones , Ratones Noqueados , Microtúbulos/metabolismo , Cuerpos Multivesiculares/metabolismo , Cuerpos Multivesiculares/ultraestructura , Miosinas/metabolismo , Linfocitos T/ultraestructura , Proteínas de Unión al GTP rab/metabolismo
17.
Microbes Infect ; 4(2): 185-8, 2002 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11880051

RESUMEN

Emil von Behring is the father of serum therapy. We present an overview of the development of this important tool in the treatment of diphtheria. In a historical context Behring's work reflects the scientific spirit of fin de siècle Berlin.


Asunto(s)
Difteria/historia , Inmunización/historia , Animales , Difteria/inmunología , Difteria/terapia , Toxoide Diftérico/historia , Toxoide Diftérico/inmunología , Alemania , Historia del Siglo XIX , Humanos , Sueros Inmunes/historia , Sueros Inmunes/inmunología , Premio Nobel
18.
Microbes Infect ; 6(8): 786-9, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15207826

RESUMEN

In 2004, we celebrate the 150th anniversary of the birth of Paul Ehrlich, considered the founder of immunology. His life and work can be divided into three creative periods: first, he developed histological staining, then he accomplished his ground-breaking work on immunology, and eventually invented chemotherapy. Paul Ehrlich can be perceived as a man whose success was not the consequence of a will to power, but of his substantial interest in science.


Asunto(s)
Alergia e Inmunología/historia , Quimioterapia/historia , Alemania , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Polonia , Sífilis/tratamiento farmacológico , Sífilis/historia
19.
J Vis Exp ; (51)2011 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-21610670

RESUMEN

Hepatic stellate cells are liver-resident cells of star-like morphology and are located in the space of Disse between liver sinusoidal endothelial cells and hepatocytes(1,2). Stellate cells are derived from bone marrow precursors and store up to 80% of the total body vitamin A(1, 2). Upon activation, stellate cells differentiate into myofibroblasts to produce extracellular matrix, thus contributing to liver fibrosis(3). Based on their ability to contract, myofibroblastic stellate cells can regulate the vascular tone associated with portal hypertension(4). Recently, we demonstrated that hepatic stellate cells are potent antigen presenting cells and can activate NKT cells as well as conventional T lymphocytes(5). Here we present a method for the efficient preparation of hepatic stellate cells from mouse liver. Due to their perisinusoidal localization, the isolation of hepatic stellate cells is a multi-step process. In order to render stellate cells accessible to isolation from the space of Disse, mouse livers are perfused in situ with the digestive enzymes Pronase E and Collagenase P. Following perfusion, the liver tissue is subjected to additional enzymatic treatment with Pronase E and Collagenase P in vitro. Subsequently, the method takes advantage of the massive amount of vitamin A-storing lipid droplets in hepatic stellate cells. This feature allows the separation of stellate cells from other hepatic cell types by centrifugation on an 8% Nycodenz gradient. The protocol described here yields a highly pure and homogenous population of stellate cells. Purity of preparations can be assessed by staining for the marker molecule glial fibrillary acidic protein (GFAP), prior to analysis by fluorescence microscopy or flow cytometry. Further, light microscopy reveals the unique appearance of star-shaped hepatic stellate cells that harbor high amounts of lipid droplets. Taken together, we present a detailed protocol for the efficient isolation of hepatic stellate cells, including representative images of their morphological appearance and GFAP expression that help to define the stellate cell entity.


Asunto(s)
Células Estrelladas Hepáticas/citología , Hígado/citología , Animales , Colagenasas/química , Proteína Ácida Fibrilar de la Glía , Células Estrelladas Hepáticas/química , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/análisis , Pronasa/química
20.
Adv Immunol ; 105: 25-62, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20510729

RESUMEN

Saposins or sphingolipid activator proteins (SAPs) are small, nonenzymatic glycoproteins that are ubiquitously present in lysosomes. SAPs comprise the five molecules saposins A-D and the GM2 activator protein. Saposins are essential for sphingolipid degradation and membrane digestion. On the one hand, they bind the respective hydrolases required to catabolize sphingolipid molecules; on the other hand, saposins can interact with intralysosomal membrane structures to render lipids accessible to their degrading enzymes. Thus, saposins bridge the physicochemical gap between lipid substrate and hydrophilic hydrolases. Accordingly, defects in saposin function can lead to lysosomal lipid accumulation. In addition to their specific functions in sphingolipid metabolism, saposins have membrane-perturbing properties. At the low pH of lysosomes, saposins get protonated and exhibit a high binding affinity for anionic phospholipids. Based on their universal principle to interact with membrane bilayers, we present the immunological functions of saposins with regard to lipid antigen presentation to CD1-restricted T cells, processing of apoptotic bodies for antigen delivery and cross-priming, as well as their potential antimicrobial impact.


Asunto(s)
Presentación de Antígeno , Glicoproteínas/metabolismo , Lisosomas/metabolismo , Saposinas/metabolismo , Esfingolípidos/metabolismo , Antígenos CD1d/análisis , Endosomas/química , Endosomas/metabolismo , Glucosilceramidasa/metabolismo , Metabolismo de los Lípidos , Activación de Linfocitos , Células T Asesinas Naturales/inmunología
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