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1.
Hepatology ; 70(5): 1804-1815, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31077406

RESUMEN

Liver-resident natural killer (LrNK) cells are a unique subset of NK cells that are distinct from conventional NK cells. However, little is known about the mechanisms by which LrNK cells mature. In this study, we discovered that LrNK cells exhibit a relatively immature phenotype and impaired cytotoxic capacity in the absence of CD8+ T cells. The provision of CD8+ T cells to Cd8-/- or Rag1-/- mice led to the restoration of LrNK cell maturation. Furthermore, co-culture with CD8+ T cells induced immature CD27+ LrNK cells to convert into mature CD27- LrNK cells, whereas blocking the interaction of CD70 and CD27 abrogated the ability of CD8+ T cells to promote the maturation of LrNK cells. Conclusion: Our findings indicate that CD8+ T cells promote the maturation of LrNK cells through the CD70-CD27 axis, and therefore highlight a previously unknown mechanism responsible for the mediation of LrNK cell maturation.


Asunto(s)
Ligando CD27/fisiología , Linfocitos T CD8-positivos/fisiología , Células Asesinas Naturales/fisiología , Hígado/citología , Animales , Células Cultivadas , Ratones , Ratones Endogámicos C57BL
2.
Breast Cancer ; 25(6): 706-716, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29948958

RESUMEN

BACKGROUND: Cancer stem cells (CSCs) are believed to form metastases. We sought to determine whether CD70 + subpopulation in human breast cancers represents the CSCs accounting for distant metastasis. METHODS: We measured the expression levels of CD70 in breast cancer cell lines and 122 primary breast cancer samples. We characterized the functional roles of CD70 + subpopulation in distant metastasis of breast cancers. RESULTS: We observed a distinct pattern of CD70 expression in a panel of primary breast carcinoma samples, indicating that CD70 serves as a biomarker of lung-specific metastasis. CD70- and CD70+ cell populations isolated from breast cancer cell lines exhibited epithelial and mesenchymal phenotypes, respectively. CD70+ cells, but not CD70- cells, possessed self-renewal and differentiation potentials. Tumorsphere formation in suspension cultures and in vivo tumorigenicity were significantly greater in CD70+ cells than in CD70- cells. Furthermore, the development of lung metastases induced by orthotopic injection was markedly increased in mice inoculated with CD70 + cells. CD70 contributed to the promotion of lung metastases by enhancing self-renewal potential of CD70 + cells. CONCLUSIONS: We isolated CSCs from primary human breast cancers and found that CD70 + subpopulations mediate lung-specific metastasis. These findings might be used to aid in selection of patients for postoperative adjuvant therapy.


Asunto(s)
Neoplasias de la Mama/patología , Ligando CD27/análisis , Neoplasias Pulmonares/secundario , Células Madre Neoplásicas/química , Adulto , Animales , Ligando CD27/fisiología , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Células Madre Neoplásicas/fisiología
3.
Int J Cardiol ; 260: 184-190, 2018 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-29622436

RESUMEN

BACKGROUND: T cells have a distinctive role in neovascularization, which consists of arteriogenesis and angiogenesis under pathological conditions and vasculogenesis under physiological conditions. However, the role of co-stimulation in T cell activation in neovascularization has yet to be established. The aim of this study was to investigate the role T cell co-stimulation and inhibition in angiogenesis, arteriogenesis and vasculogenesis. METHODS AND RESULTS: Hind limb ischemia was induced by double ligation of the left femoral artery in mice and blood flow recovery was measured with Laser Doppler Perfusion Imaging in control, CD70-/-, CD80/86-/-, CD70/80/86-/- and CTLA4+/- mice. Blood flow recovery was significantly impaired in mice lacking CD70 compared to control mice, but was similar in CD80/86-/-, CTLA4+/- and control mice. Mice lacking CD70 showed impaired vasculogenesis, since the number of pre-existing collaterals was reduced as observed in the pia mater compared to control mice. In vitro an impaired capability of vascular smooth muscle cells (VSMC) to activate T cells was observed in VSMC lacking CD70. Furthermore, CD70-/-, CD80/86-/- and CD70/80/86-/- mice showed reduced angiogenesis in the soleus muscle 10 days after ligation. Arteriogenesis was also decreased in CD70-/- compared to control mice 10 and 28 days after surgery. CONCLUSIONS: The present study is the first to describe an important role for T cell activation via co-stimulation in angiogenesis, arteriogenesis and vasculogenesis, where the CD27-CD70 T cell co-stimulation pathway appears to be the most important co-stimulation pathway in pre-existing collateral formation and post-ischemic blood flow recovery, by arteriogenesis and angiogenesis.


Asunto(s)
Ligando CD27/fisiología , Miembro Posterior/diagnóstico por imagen , Isquemia/diagnóstico por imagen , Neovascularización Patológica/diagnóstico por imagen , Linfocitos T/fisiología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología , Animales , Ligando CD27/deficiencia , Miembro Posterior/irrigación sanguínea , Isquemia/fisiopatología , Flujometría por Láser-Doppler/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Patológica/fisiopatología , Neovascularización Fisiológica/fisiología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/deficiencia
4.
Immunity ; 47(5): 848-861.e5, 2017 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-29126798

RESUMEN

CD4+ T cells optimize the cytotoxic T cell (CTL) response in magnitude and quality, by unknown molecular mechanisms. We here present the transcriptomic changes in CTLs resulting from CD4+ T cell help after anti-cancer vaccination or virus infection. The gene expression signatures revealed that CD4+ T cell help during priming optimized CTLs in expression of cytotoxic effector molecules and many other functions that ensured efficacy of CTLs throughout their life cycle. Key features included downregulation of PD-1 and other coinhibitory receptors that impede CTL activity, and increased motility and migration capacities. "Helped" CTLs acquired chemokine receptors that helped them reach their tumor target tissue and metalloprotease activity that enabled them to invade into tumor tissue. A very large part of the "help" program was instilled in CD8+ T cells via CD27 costimulation. The help program thus enhances specific CTL effector functions in response to vaccination or a virus infection.


Asunto(s)
Ligando CD27/fisiología , Linfocitos T CD4-Positivos/fisiología , Linfocitos T Citotóxicos/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología , Animales , Receptor 1 de Quimiocinas CX3C/fisiología , Diferenciación Celular , Movimiento Celular , Regulación hacia Abajo , Ratones , Ratones Endogámicos C57BL , Receptores CXCR4/fisiología
5.
J Exp Med ; 214(2): 269-283, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-28108590

RESUMEN

The mammalian immune system has evolved over many millennia to be best equipped to protect the host from pathogen infection. In many cases, host and pathogen have coevolved, each acquiring sophisticated ways of inducing or protecting from disease. Epstein-Barr virus (EBV) is a human herpes virus that infects >90% of individuals. Despite its ubiquity, infection by EBV is often subclinical; this invariably reflects the necessity of the virus to preserve its host, balanced with sophisticated host immune mechanisms that maintain viral latency. However, EBV infection can result in various, and often fatal, clinical sequelae, including fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis, lymphoproliferative disease, organomegaly, and/or malignancy. Such clinical outcomes are typically observed in immunosuppressed individuals, with the most extreme cases being Mendelian primary immunodeficiencies (PIDs). Although these conditions are rare, they have provided critical insight into the cellular, biochemical, and molecular requirements for robust and long-lasting immunity against EBV infection. Here, we review the virology of EBV, mechanisms underlying disease pathogenesis in PIDs, and developments in immune cell-mediated therapy to treat disorders associated with or induced by EBV infection.


Asunto(s)
Herpesvirus Humano 4/inmunología , Inmunidad Adaptativa , Animales , Ligando CD27/fisiología , Linfocitos T CD4-Positivos/inmunología , Humanos , Síndromes de Inmunodeficiencia/etiología , Inmunoterapia Adoptiva , Células Asesinas Naturales/inmunología , Trastornos Linfoproliferativos/genética , Transducción de Señal , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología
6.
J Exp Med ; 214(2): 359-380, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-28031480

RESUMEN

Aberrant proliferation, symmetric self-renewal, increased survival, and defective differentiation of malignant blasts are key oncogenic drivers in acute myeloid leukemia (AML). Stem cell gene signatures predict poor prognosis in AML patients; however, with few exceptions, these deregulated molecular pathways cannot be targeted therapeutically. In this study, we demonstrate that the TNF superfamily ligand-receptor pair CD70/CD27 is expressed on AML blasts and AML stem/progenitor cells. CD70/CD27 signaling in AML cells activates stem cell gene expression programs, including the Wnt pathway, and promotes symmetric cell divisions and proliferation. Soluble CD27, reflecting the extent of CD70/CD27 interactions in vivo, was significantly elevated in the sera of newly diagnosed AML patients and is a strong independent negative prognostic biomarker for overall survival. Blocking the CD70/CD27 interaction by mAb induced asymmetric cell divisions and differentiation in AML blasts and AML stem/progenitor cells, inhibited cell growth and colony formation, and significantly prolonged survival in murine AML xenografts. Importantly, hematopoietic stem/progenitor cells from healthy BM donors express neither CD70 nor CD27 and were unaffected by blocking mAb treatment. Therefore, targeting CD70/CD27 signaling represents a promising therapeutic strategy for AML.


Asunto(s)
Crisis Blástica/etiología , Ligando CD27/fisiología , Leucemia Mieloide Aguda/patología , Transducción de Señal/fisiología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología , Anciano , Animales , Anticuerpos Monoclonales/uso terapéutico , Ligando CD27/antagonistas & inhibidores , Quinasas del Centro Germinal , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Ratones , Persona de Mediana Edad , Proteínas Serina-Treonina Quinasas/fisiología , Factor 2 Asociado a Receptor de TNF/fisiología , Células Tumorales Cultivadas , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/antagonistas & inhibidores , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/sangre , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Vía de Señalización Wnt/fisiología
7.
J Exp Med ; 214(1): 73-89, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-28011863

RESUMEN

Epstein-Barr virus (EBV) infection in humans is a major trigger of malignant and nonmalignant B cell proliferations. CD27 is a co-stimulatory molecule of T cells, and inherited CD27 deficiency is characterized by high susceptibility to EBV infection, though the underlying pathological mechanisms have not yet been identified. In this study, we report a patient suffering from recurrent EBV-induced B cell proliferations including Hodgkin's lymphoma because of a deficiency in CD70, the ligand of CD27. We show that EBV-specific T lymphocytes did not expand properly when stimulated with CD70-deficient EBV-infected B cells, whereas expression of CD70 in B cells restored expansion, indicating that CD70 on B cells but not on T cells is required for efficient proliferation of T cells. CD70 was found to be up-regulated on B cells when activated and during EBV infection. The proliferation of T cells triggered by CD70-expressing B cells was dependent on CD27 and CD3 on T cells. Importantly, CD27-deficient T cells failed to proliferate when stimulated with CD70-expressing B cells. Thus, the CD70-CD27 pathway appears to be a crucial component of EBV-specific T cell immunity and more generally for the immune surveillance of B cells and may be a target for immunotherapy of B cell malignancies.


Asunto(s)
Ligando CD27/fisiología , Infecciones por Virus de Epstein-Barr/inmunología , Transducción de Señal/fisiología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología , Linfocitos B/inmunología , Ligando CD27/deficiencia , Ligando CD27/genética , Niño , Codón sin Sentido , Humanos , Activación de Linfocitos , Masculino , Receptores de Antígenos de Linfocitos T/fisiología , Linfocitos T/inmunología
8.
Cancer Res ; 76(20): 6017-6029, 2016 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-27569212

RESUMEN

Certain cytotoxic chemotherapeutic drugs are immunogenic, stimulating tumor immunity through mechanisms that are not completely understood. Here we show how the DNA-damaging drug cisplatin modulates tumor immunity. At the maximum tolerated dose (MTD), cisplatin cured 50% of mice with established murine TC-1 or C3 tumors, which are preclinical models of human papillomavirus (HPV)-associated cancer. Notably, the curative benefit of cisplatin relied entirely upon induction of tumor-specific CD8+ T cells. Mechanistic investigations showed that cisplatin stimulated tumor infiltration of inflammatory antigen-presenting cells (APC) expressing relatively higher levels of the T-cell costimulatory ligands CD70, CD80, and CD86. Cell death triggered by cisplatin was associated with the release of at least 19 proteins in the tumor environment that could act as damage-associated molecular patterns and upregulate costimulatory molecules, either alone or in concert, but the responsible proteins remain unknown. Essentially, the curative effect of cisplatin was abrogated in mice lacking expression of CD80 and CD86 on APCs. Furthermore, cisplatin treatment was improved by CTLA-4 blockade, which increases the availability of CD80/86 to bind to CD28. In contrast, there was no effect of CD27 stimulation, which replaces CD70 interaction. At the cisplatin MTD, cure rates could also be increased by vaccination with synthetic long peptides, whereas cures could also be achieved at similar rates at 80% of the MTD with reduced side effects. Our findings reveal an essential basis for the immunogenic properties of cisplatin, which are mediated by the induction of costimulatory signals for CD8+ T-cell-dependent tumor destruction. Cancer Res; 76(20); 6017-29. ©2016 AACR.


Asunto(s)
Antineoplásicos/uso terapéutico , Antígeno B7-1/fisiología , Antígeno B7-2/fisiología , Linfocitos T CD8-positivos/inmunología , Cisplatino/uso terapéutico , Neoplasias Experimentales/tratamiento farmacológico , Animales , Células Presentadoras de Antígenos/fisiología , Ligando CD27/fisiología , Interferón gamma/biosíntesis , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide/fisiología , Neoplasias Experimentales/inmunología , Vacunación
9.
Br J Cancer ; 114(1): 63-70, 2016 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-26671750

RESUMEN

BACKGROUND: CD70 is a costimulatory molecule of the tumour necrosis factor family expressed in activated immune cells and some solid tumours. In lymphocytes CD70 triggers T cell-mediated cytotoxicity and mitogen-activated protein kinase phosphorylation. METHODS: We evaluated the expression of CD70 in biopsies and melanoma cell lines. Using melanoma cell lines positive or not for CD70, we analysed CD70 function on melanoma progression. RESULTS: We report CD70 expression in human melanoma cell lines and tumour cells from melanoma biopsies. This expression was observed in 95% of primary melanomas but only 37% of metastases. Both monomeric and trimeric forms of CD70 were detected in tumour cell membrane fractions, whereas cytoplasmic fractions contained almost exclusively monomeric CD70. In vitro and in vivo experiments demonstrated that CD70 expression inhibited melanoma cell migration, invasion and pulmonary metastasis implantation independently of the tumour immune microenvironment. Increasing the levels of the trimeric form of CD70 through monoclonal antibody binding led to an increase in CD70+ melanoma cell invasiveness through MAPK pathway activation, RhoE overexpression, ROCK1 and MYPT1 phosphorylation decrease, and stress fibres and focal adhesions disappearance. CONCLUSIONS: Our results describe a new non-immunological function of melanoma-expressed CD70, which involves melanoma invasiveness through MAPK pathway, RhoE and cytoskeletal modulation.


Asunto(s)
Ligando CD27/fisiología , Melanoma/patología , Animales , Ligando CD27/análisis , Línea Celular Tumoral , Movimiento Celular , Citoesqueleto/fisiología , Femenino , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Ratones Endogámicos C57BL , Invasividad Neoplásica , Metástasis de la Neoplasia , Proteínas de Unión al GTP rho/fisiología , Quinasas Asociadas a rho/fisiología
10.
Eur J Immunol ; 45(12): 3289-301, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26461455

RESUMEN

CD70-mediated stimulation of CD27 is an important cofactor of CD4(+) T-cell licensed dendritic cells (DCs). However, it is unclear how CD70-mediated stimulation of T cells is integrated with signals that emanate from signal 3 pathways, such as type-1 interferon (IFN-1) and IL-12. We find that while stimulation of CD27 in isolation drives weak Eomesodermin(hi) T-bet(lo) CD8(+) T-cell responses to OVA immunization, profound synergistic expansion is achieved by cotargeting TLR. This cooperativity can substantially boost antiviral CD8(+) T-cell responses during acute infection. Concomitant stimulation of TLR significantly increases per cell IFN-γ production and the proportion of the population with characteristics of short-lived effector cells, yet also promotes the ability to form long-lived memory. Notably, while IFN-1 contributes to the expression of CD70 on DCs, the synergy between CD27 and TLR stimulation is dependent upon IFN-1's effect directly on CD8(+) T cells, and is associated with the increased expression of T-bet in T cells. Surprisingly, we find that IL-12 fails to synergize with CD27 stimulation to promote CD8(+) T-cell expansion, despite its capacity to drive effector CD8(+) T-cell differentiation. Together, these data identify complex interactions between signal 3 and costimulatory pathways, and identify opportunities to influence the differentiation of CD8(+) T-cell responses.


Asunto(s)
Ligando CD27/fisiología , Linfocitos T CD8-positivos/inmunología , Interferón Tipo I/farmacología , Proteínas de Dominio T Box/fisiología , Animales , Memoria Inmunológica , Interleucina-12/farmacología , Ratones , Ratones Endogámicos C57BL , Receptores Toll-Like/fisiología
11.
Scand J Immunol ; 79(6): 415-22, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24684541

RESUMEN

Antigen-loaded dendritic cells (DCs) used as anticancer vaccine holds promise for therapy, but needs to be optimized. The most frequently described DC vaccine is being matured with a cocktail containing prostaglandin E2 (PGE2 DC). However, even though PGE2 DCs express both costimulatory and migratory receptors, their IL-12p70-prodcution is low, leading to an insufficient Th1 immune response. As an alternative, α-type-1 polarized DCs (αDC1s) have shown a superior production of IL-12p70 and subsequent activation of effector cells. From chronic lymphocytic leukaemia (CLL) patients, αDC1s can be generated to induce a functional Th1-immune response. Yet, another costimulatory receptor, CD70, appears to be essential for optimal DC function by promotion of T cell survival and function. So far, PGE2 is suggested as one of the most important factors for the induction of CD70 expression on DCs. Therefore, we wanted to investigate whether αDC1s have the ability to express functional CD70. We found that CD70 expression on αDC1s could be upregulated in the same manner as PGE2 DCs. In an allogeneic mixed leucocyte reaction, we found that antibody-blocking of CD70 on αDC1s from controls reduced effector cell proliferation although this could not be found when using CLL αDC1s. Nevertheless, CD70-blocking of αDC1s from both controls and patients with CLL had a negative influence on the production of both IL-12p70 and the Th1 cytokine IFN-γ, while the production of the Th2 cytokine IL-5 was enhanced. Together, this study further suggests that αDC1s should be considered as a suitable candidate for clinical antitumour vaccine strategies in patients with CLL.


Asunto(s)
Ligando CD27/fisiología , Células Dendríticas/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Ligando CD27/análisis , Polaridad Celular , Dinoprostona/análisis , Humanos , Interleucina-12/biosíntesis , Células TH1/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología
12.
Leukemia ; 28(9): 1872-84, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24569779

RESUMEN

Transforming growth factor beta (TGF-ß) has an important role in mediating T-cell suppression in B-cell non-Hodgkin lymphoma (NHL). However, the underlying mechanism responsible for TGF-ß-mediated inhibition of effector memory T (Tm) cells is largely unknown. As reported here, we show that exhaustion is a major mechanism by which TGF-ß inhibits Tm cells, and TGF-ß mediated exhaustion is associated with upregulation of CD70. We found that TGF-ß upregulates CD70 expression on effector Tm cells while it preferentially induces Foxp3 expression in naive T cells. CD70 induction by TGF-ß is Smad3-dependent and involves IL-2/Stat5 signaling. CD70+ T cells account for TGF-ß-induced exhaustion of effector Tm cells. Both TGF-ß-induced and preexisting intratumoral CD70+ effector Tm cells from B-cell NHL have an exhausted phenotype and express higher levels of PD-1 and TIM-3 compared with CD70- T cells. Signaling transduction, proliferation and cytokine production are profoundly decreased in these cells, and they are highly susceptible to apoptosis. Clinically, intratumoral CD70-expressing T cells are prevalent in follicular B-cell lymphoma (FL) biopsy specimens, and increased numbers of intratumoral CD70+ T cells correlate with an inferior patient outcome. These findings confirm TGF-ß-mediated effector Tm cell exhaustion as an important mechanism of immune suppression in B-cell NHL.


Asunto(s)
Ligando CD27/fisiología , Memoria Inmunológica , Linfoma de Células B/inmunología , Linfocitos T/inmunología , Factor de Crecimiento Transformador beta/farmacología , Apoptosis , Ligando CD27/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Receptor 2 Celular del Virus de la Hepatitis A , Humanos , Interleucina-2/fisiología , Proteínas de la Membrana/análisis , Receptor de Muerte Celular Programada 1/análisis , Factor de Transcripción STAT5/fisiología , Transducción de Señal , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología
13.
J Immunol ; 191(4): 1976-83, 2013 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-23842750

RESUMEN

Regulatory T cells (Tregs) counteract anticancer immune responses through a number of mechanisms, limiting dendritic cell (DC)-based anticancer immunotherapy. In this study, we investigated the influence of various DC activation stimuli on the Treg functionality. We compared DCs activated by electroporation with mRNA encoding constitutively active TLR4 (caTLR4) and CD40 ligand (DiMix-DCs), or these factors together with mRNA encoding the costimulatory molecule CD70 (TriMix-DCs) with DCs maturated in the presence of a mixture of inflammatory cytokines (DCs maturated with a combination of the cytokines IL-1ß, IL-6, TNF-α, and PGE2) for their ability to counteract Tregs on different levels. We first demonstrated that there was no difference in the extent of Treg induction starting from CD4(+)CD25(-) T cells under the influence of the different DC maturation stimuli. Second, we showed that both DiMix- and TriMix-DCs could partly alleviate Treg inhibition of CD8(+) T cells. Third, we observed that CD8(+) T cells that had been precultured with DiMix-DCs or TriMix-DCs were partially protected against subsequent Treg suppression. Finally, we showed that Tregs cocultured in the presence of TriMix-DCs, but not DiMix-DCs, partially lost their suppressive capacity. This was accompanied by a decrease in CD27 and CD25 expression on Tregs, as well as an increase in the expression of T-bet and secretion of IFN-γ, TNF-α, and IL-10, suggesting a shift of the Treg phenotype toward a Th1 phenotype. In conclusion, these data suggest that TriMix-DCs are not only able to suppress Treg functions, but moreover could be able to reprogram Tregs to Th1 cells under certain circumstances.


Asunto(s)
Ligando CD27/fisiología , Ligando de CD40/fisiología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Tolerancia Inmunológica/inmunología , Linfopoyesis/fisiología , Linfocitos T Reguladores/inmunología , Receptor Toll-Like 4/fisiología , Ligando CD27/genética , Linfocitos T CD4-Positivos/citología , Ligando de CD40/genética , Diferenciación Celular/efectos de los fármacos , División Celular , Células Cultivadas , Técnicas de Cocultivo , Citocinas/farmacología , Células Dendríticas/metabolismo , Electroporación , Humanos , Inmunofenotipificación , Activación de Linfocitos , MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 1/fisiología , Monocitos/citología , Monocitos/efectos de los fármacos , ARN Mensajero/administración & dosificación , ARN Mensajero/genética , Proteínas Recombinantes de Fusión/metabolismo , Linfocitos T Reguladores/citología , Células TH1/inmunología , Receptor Toll-Like 4/genética
14.
Blood ; 118(9): 2578-88, 2011 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-21725055

RESUMEN

Anemia of chronic disease is a complication accompanying many inflammatory diseases. The proinflammatory cytokine IFN-γ has been implicated in this form of anemia, but the underlying mechanism remains unclear. Here we describe a novel mouse model for anemia of chronic disease, in which enhanced CD27-mediated costimulation strongly increases the formation of IFN-γ-producing effector T cells, leading to a progressive anemia. We demonstrate that the anemia in these mice is fully dependent on IFN-γ and that this cytokine reduces both the life span and the formation of red blood cells. Molecular analysis revealed that IFN-γ induces expression of the transcription factors of interferon regulatory factor-1 (IRF-1) and PU.1 in both murine and human erythroid precursors. We found that, on IFN-γ stimulation, IRF-1 binds to the promoter of SPI.1 (PU.1) and induces PU.1 expression, leading to inhibition of erythropoiesis. Notably, down-regulation of either IRF-1 or PU.1 expression is sufficient to overcome IFN-γ-induced inhibition of erythropoiesis. These findings reveal a molecular mechanism by which chronic exposure to IFN-γ induces anemia.


Asunto(s)
Anemia/etiología , Modelos Animales de Enfermedad , Envejecimiento Eritrocítico/efectos de los fármacos , Células Precursoras Eritroides/efectos de los fármacos , Eritropoyesis/efectos de los fármacos , Factor 1 Regulador del Interferón/fisiología , Interferón gamma/farmacología , Proteínas Proto-Oncogénicas/fisiología , Transactivadores/fisiología , Animales , Ligando CD27/genética , Ligando CD27/fisiología , Enfermedad Crónica , Ensayo de Unidades Formadoras de Colonias , Células Precursoras Eritroides/citología , Factor 1 Regulador del Interferón/antagonistas & inhibidores , Factor 1 Regulador del Interferón/biosíntesis , Factor 1 Regulador del Interferón/sangre , Factor 1 Regulador del Interferón/genética , Macrófagos/fisiología , Ratones , Ratones Endogámicos C57BL , Fagocitosis , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas/sangre , Proteínas Proto-Oncogénicas/genética , ARN Interferente Pequeño/farmacología , Proteínas Recombinantes de Fusión/fisiología , Organismos Libres de Patógenos Específicos , Transactivadores/antagonistas & inhibidores , Transactivadores/biosíntesis , Transactivadores/sangre , Transactivadores/genética
15.
J Virol ; 85(13): 6168-74, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21507976

RESUMEN

T cell costimulation is important for T cell activation. The CD27/CD70 pathway contributes to effector and memory T cell development and is involved in T cell and B cell activation. CD27/CD70 is known for having opposing roles during different models of antigenic challenges. During primary T cell responses to influenza virus infection or during tumor challenges, CD27/CD70 costimulation has a positive role on T cell responses. However, during some chronic infections, constitutive triggering of this signaling pathway has a negative role on T cell responses. It is currently unclear what specific characteristic of an antigen determines the outcome of CD27/CD70 costimulation. We investigated the effect of a transient CD70 blockade during an acute or a chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Blockade of this pathway during acute LCMV infection (Armstrong strain) resulted in delayed T cell responses and decreased CD127 (interleukin-7 receptor α [IL-7Rα] chain) conversion. Upregulation of CD127 is an important event in T cell differentiation that heralds the passage of an effector T cell to a long-lived memory T cell. In contrast to the reduced CD8 T cell responses after CD70 blockade during acute infection, CD70 blockade during chronic LCMV infection resulted in increased CD8 T cell responses. Our data show the dual roles of this costimulatory pathway in acute versus persistent antigen challenge. Our findings suggest that antigen persistence may determine the effect of CD27/CD70 signaling on CD8 T cell responses. Tailored triggering or blockade of this costimulatory pathway may be important in vaccination regimens against acute or chronic pathogens.


Asunto(s)
Ligando CD27/inmunología , Linfocitos T CD8-positivos/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Transducción de Señal , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Enfermedad Aguda , Animales , Ligando CD27/fisiología , Diferenciación Celular , Enfermedad Crónica , Femenino , Activación de Linfocitos , Coriomeningitis Linfocítica/virología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología
16.
J Invest Dermatol ; 131(6): 1252-61, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21490618

RESUMEN

The interaction between CD27 and CD70 provides a costimulatory signal for T-cell survival. Although the role of CD27 signaling in CD8(+) T cells has been well defined, its role in CD4(+) T cells is relatively unknown. Here, we report that CD70 is specifically expressed on differentiated T-helper (Th)1 cells, but not on Th2 cells. Upon activation, CD70 expression increased markedly on Th1 cells, but remained undetectable on Th2 cells. We demonstrate that CD27 is involved in naive T-cell expansion in Th1-type, but not in Th2-type, immune responses as in vivo treatment with anti-CD70 monoclonal antibody at induction resulted in a significant reduction of delayed-type and contact hypersensitivity responses, but not asthmatic responses. In both Th1-type responses, during the priming phase, CD70 was detected at earlier time points on dendritic cells (DCs) and at later time points on CD4(+) T cells. Our results indicate that CD70 may be useful as a marker to distinguish Th1 from Th2 cells. More importantly, CD27 function may be controlled by the differentially regulated kinetics of CD70 expression on DCs and CD4(+) T cells, and Th1 cell-specific CD70 expression may be involved in an amplification loop for polarized Th1-type immune responses through T cell-T cell interactions.


Asunto(s)
Ligando CD27/fisiología , Células TH1/inmunología , Células Th2/inmunología , Animales , Asma/inmunología , Ligando CD27/análisis , Citocinas/biosíntesis , Dermatitis por Contacto/etiología , Femenino , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/análisis
17.
J Leukoc Biol ; 89(2): 195-203, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20699361

RESUMEN

The CD70/CD27 axis has gained increasing interest among the immunologists, because of its capacity to regulate immunity versus tolerance. Recent studies clearly show that expression of CD70 may prevent tolerance induced by antigen presentation in the steady-state, i.e., by nonactivated DCs. In addition, CD27 signaling appears critical for T cell expansion and survival and therefore, induction of long-term memory. It contributes to germinal center formation, B cell activation, and production of neutralizing antibodies but can also be subverted by viruses, in particular, during chronic infections. The potential role of the CD27/CD70 pathway in the course of inflammatory diseases, as in EAE, arthritis, and inflammatory bowel disease models, suggests that CD70 may be a target for immune intervention. Conversely, the potency of costimulation through CD27 suggests that the CD27/CD70 axis could be exploited for the design of anti-cancer vaccines.


Asunto(s)
Inmunidad Adaptativa/inmunología , Ligando CD27/fisiología , Tolerancia Inmunológica , Inmunidad Innata/inmunología , Activación de Linfocitos/inmunología , Transducción de Señal/inmunología , Inmunidad Adaptativa/genética , Animales , Ligando CD27/deficiencia , Ligando CD27/genética , Humanos , Tolerancia Inmunológica/genética , Inmunidad Humoral/genética , Inmunidad Humoral/inmunología , Inmunidad Innata/genética , Activación de Linfocitos/genética , Transducción de Señal/genética , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
18.
J Leukoc Biol ; 88(1): 69-78, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20354106

RESUMEN

This study tested the hypothesis that individual myeloid subsets have a differential ability to maintain memory CD8 T cells via IL-15. Although DCs support IL-15-mediated homeostasis of memory CD8 T cells in vivo, whether various DC subsets and other myeloid cells similarly mediate homeostasis is unknown. Therefore, we studied the ability of different myeloid cells to maintain memory CD8 T cells in vitro. Using an in vitro cocoulture system that recapitulated known roles of DCs and IL-15 on memory CD8 T cells, all in vitro-derived or ex vivo-isolated DCs maintained CD8 T cells better than rIL-15 alone, and FLT-3L-DCs are the most efficient compared with GM-DCs, BM-derived macrophages, or freshly isolated DCs. Although FLT-3L-DCs were the least effective at inducing CD8 T cell proliferation, FLT-3L-DCs promoted better CD8 T cell survival and increased Bcl-2 and MCL-2 expression in CD8 T cells. T cell maintenance correlated only partially with DC expression of IL-15Ralpha and IL-15, suggesting that DCs provided additional support signals. Indeed, in the absence of IL-15 signals, CD70/CD27 further supported CD8 T cell maintenance. IFN-alpha enhanced CD70 expression by DCs, resulting in increased proliferation of CD8 T cells. Overall, this study supports our hypothesis by demonstrating that specific DC subtypes had a greater capacity to support memory CD8 T cell maintenance and did so through different mechanisms. Furthermore, this study shows that IL-15 trans-presentation can work in conjunction with other signals, such as CD70/CD27 interactions, to mediate CD8 T cell homeostasis efficiently.


Asunto(s)
Linfocitos T CD8-positivos/fisiología , Células Dendríticas/fisiología , Memoria Inmunológica , Macrófagos/fisiología , Animales , Ligando CD27/fisiología , Proliferación Celular , Supervivencia Celular , Interferón-alfa/farmacología , Subunidad alfa del Receptor de Interleucina-15/fisiología , Interleucina-5/farmacología , Proteínas de la Membrana/farmacología , Ratones , Ratones Endogámicos C57BL , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología
19.
Brain Res ; 1317: 236-45, 2010 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-20045400

RESUMEN

Ligation of CD27, a member of the tumor necrosis factor (TNF) receptor family, by its ligand CD70 is thought to be important in T cell activation, expansion and survival, B cell activation, and NK cell activation. We examined the role of CD70 in Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) mice. Blocking of CD70 in effector phase by anti-CD70 monoclonal antibody (mAb) suppressed the development of TMEV-IDD. The number of IFN-gamma- or TNF-alpha-producing cells in the spleen and mRNA levels of IFN-gamma and TNF-alpha in spinal cord were decreased in mice treated with anti-CD70 mAb at the effector phase. In contrast, treatment with anti-CD70 mAb in induction phase failed to reduce these responses, compared to nonspecific IgG-treated control mice. These data suggest that CD70 is critically involved in the pathogenesis of TMEV-IDD and that antibodies against CD70 could be a novel therapeutic approach in the clinical treatment of demyelinating diseases such as human multiple sclerosis.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Ligando CD27/inmunología , Infecciones por Cardiovirus/prevención & control , Enfermedades Desmielinizantes/prevención & control , Factores Inmunológicos/uso terapéutico , Theilovirus , Animales , Ligando CD27/fisiología , Infecciones por Cardiovirus/inmunología , Infecciones por Cardiovirus/metabolismo , Citocinas/metabolismo , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/metabolismo , Femenino , Interferón gamma/metabolismo , Ratones , ARN Mensajero/metabolismo , Médula Espinal/inmunología , Médula Espinal/metabolismo , Bazo/inmunología , Bazo/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismo
20.
J Clin Invest ; 120(1): 168-78, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19955658

RESUMEN

Immunity to infections relies on clonal expansion of CD8+ T cells, their maintenance as effector CTLs, and their selection into a memory population. These processes rely on delivery of survival signals to activated CD8+ T cells. We here reveal the mechanism by which costimulatory CD27-CD70 interactions sustain survival of CD8+ effector T cells in infected tissue. By unbiased genome-wide gene expression analysis, we identified the Il2 gene as the most prominent CD27 target gene in murine CD8+ T cells. In vitro, CD27 directed IL-2 expression and promoted clonal expansion of primed CD8+ T cells exclusively by IL-2-dependent survival signaling. In mice intranasally infected with influenza virus, Cd27-/- CD8+ effector T cells displayed reduced IL-2 production, accompanied by impaired accumulation in lymphoid organs and in the lungs, which constitute the tissue effector site. Reconstitution of Cd27-/- CD8+ T cells with the IL2 gene restored their accumulation to wild-type levels in the lungs, but it did not rescue their accumulation in lymphoid organs. Competition experiments showed that the IL-2 produced under the control of CD27 supported effector CD8+ T cell survival in the lungs in an autocrine manner. We conclude that CD27 signaling directs the IL-2 production that is reportedly essential to sustain survival of virus-specific CTLs in nonlymphoid tissue.


Asunto(s)
Interleucina-2/biosíntesis , Infecciones por Orthomyxoviridae/inmunología , Linfocitos T Citotóxicos/fisiología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología , Animales , Ligando CD27/fisiología , Supervivencia Celular , Células Cultivadas , Interferón gamma/biosíntesis , Interleucina-2/genética , Ratones , Ratones Endogámicos C57BL , Receptores de Interleucina-2/fisiología
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