RESUMEN
Coronavirus disease 2019 (COVID-19) is a potentially life-threatening infection characterized by excessive inflammation, coagulation disorders and organ damage. A dysregulated myeloid cell compartment is one of the most striking immunopathologic signatures of this newly emerged infection. A growing number of studies are reporting on the expansion of myeloid cells with immunoregulatory activities in the periphery and airways of COVID-19 patients. These cells share phenotypic and functional similarities with myeloid-derived suppressor cells (MDSCs), which were first described in cancer patients. MDSCs are a heterogeneous population of pathologically activated myeloid cells that exert immunosuppressive activities against mainly effector T cells. The increased frequency of these cells in COVID-19 patients suggests that they are involved in immune regulation during this infection. In this article, we review the current findings on MDSCs in COVID-19 and discuss the complex role of these cells in the immunopathology of COVID-19.
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COVID-19 , Células Supresoras de Origen Mieloide , Humanos , Inflamación , SARS-CoV-2 , Linfocitos TRESUMEN
Impaired NK cytotoxicity has been linked to poor cancer prognosis, but its mechanisms are not clearly established. Increasing data demonstrate that NK cells lose cytotoxicity after interaction with NK cell-sensitive tumor cells. In this paper, we provide evidence that the human adenocarcinoma cell line MiaPaCa2 and TNFα and TGFß-treated MiaPaCa2 cultures (MiaPaCa2-TT) induced functional anergy of NK cells via FGL2 protein. MiaPaCa2-TT cultures decreased expression of IFNγ, CD107a, DNAM-1, and stimulated expression of PD1 by NK cells, as well as inhibited their cytotoxic activity in a greater manner compared to the parental culture. More importantly, we found that co-cultivation with anergized NK cells decreased expression of IFNγ and CD107a by naïve NK cells, which supports the hypothesis of NK cell functional anergy transmission. The obtained results suggest a mechanism by which tumor cells may inhibit cytotoxic functions of tumor-infiltrating and circulating NK cells in cancer.Abbreviations: CFSE: Carboxyfluorescein diacetate succinimidyl ester; CSCs: Cancer stem cells; FGL2: Fibrinogen-like protein 2; mAbs: Monoclonal antibodies; MiaPaCa2: Human adenocarcinoma cell line; MiaPaCa2-ТТ: Adenocarcinoma cell line MiaPaCa2 cells stimulated with TNFα and TGFß-1; PI: Propidium iodide; TGFß: Transforming growth factor beta; TME: Tumor microenvironment; TNFα: Tumor necrosis factor alfa.
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Células Asesinas Naturales , Receptores Fc , Línea Celular Tumoral , Anergia Clonal , Citotoxicidad Inmunológica , Fibrinógeno , Humanos , Células Madre NeoplásicasRESUMEN
Human rhinovirus (RV) is a major risk factor for chronic obstructive pulmonary disease (COPD) and asthma exacerbations. The exploration of RV pathogenesis has been hampered by a lack of disease-relevant model systems. We performed a detailed characterization of host responses to RV infection in human lung tissue ex vivo and investigated whether these responses are disease relevant for patients with COPD and asthma. In addition, impact of the viral replication inhibitor rupintrivir was evaluated. Human precision-cut lung slices (PCLS) were infected with RV1B with or without rupintrivir. At Days 1 and 3 after infection, RV tissue localization, tissue viability, and viral load were determined. To characterize host responses to infection, mediator and whole genome analyses were performed. RV successfully replicated in PCLS airway epithelial cells and induced both antiviral and proinflammatory cytokines such as IFNα2a, CXCL10, CXCL11, IFN-γ, TNFα, and CCL5. Genomic analyses revealed that RV not only induced antiviral immune responses but also triggered changes in epithelial cell-associated pathways. Strikingly, the RV response in PCLS was reflective of gene expression changes described in patients with COPD and asthma. Although RV-induced host immune responses were abrogated by rupintrivir, RV-triggered epithelial processes were largely refractory to antiviral treatment. Detailed analysis of RV-infected human PCLS and comparison with gene signatures of patients with COPD and asthma revealed that the human RV PCLS model represents disease-relevant biological mechanisms that can be partially inhibited by a well-known antiviral compound and provide an outstanding opportunity to evaluate novel therapeutics.
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Asma/genética , Interacciones Huésped-Patógeno/genética , Pulmón/virología , Infecciones por Picornaviridae/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Anciano , Antivirales/farmacología , Asma/patología , Bronquios/patología , Bronquios/fisiología , Células Epiteliales/patología , Células Epiteliales/virología , Femenino , Perfilación de la Expresión Génica , Genoma Humano , Humanos , Isoxazoles/farmacología , Pulmón/fisiología , Masculino , Persona de Mediana Edad , Fenilalanina/análogos & derivados , Fenilalanina/farmacología , Infecciones por Picornaviridae/tratamiento farmacológico , Infecciones por Picornaviridae/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Pirrolidinonas/farmacología , Rhinovirus/patogenicidad , Valina/análogos & derivados , Valina/farmacologíaRESUMEN
Heavy metal pollution is rapidly increasing in the environment. It has been shown that exposure to vanadium and chromium is able to alter the immune response. Nevertheless, the mechanisms by which these metal pollutants mediate their immunomodulatory effects are not completely understood. Herein, we examined the effect of ammonium metavanadate and potassium dichromate on the development of an inflammatory response caused by subcutaneous injection of turpentine oil. We demonstrated that pretreatment of rats with ammonium metavanadate and potassium dichromate for two weeks prior to initiation of the inflammatory response resulted in a wider zone of necrosis surrounding the site of inflammation. The acute inflammatory process in the combined model was characterized by elevated serum levels of IL-10 and decreased serum levels of IL-6 as compared to rats not treated with ammonium metavanadate and potassium dichromate. Ammonium metavanadate and potassium dichromate administration induced a decrease in the proportion of splenic His48HighCD11b/c+ myeloid cells accompanied by a reduced infiltration of the wound with neutrophils. Further analysis showed decreased proportions of CD3+CD4+IFNγ+ and CD3+CD4+IL-4+ T cells in the rats with combined model as compared to inflamed rats not treated with ammonium metavanadate and potassium dichromate. The data suggest that consumption of vanadium and chromium compounds disrupts the inflammatory response through an altered balance of pro- and anti-inflammatory cytokines and inhibition of effector T cell activation and neutrophil expansion.
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Inflamación/prevención & control , Dicromato de Potasio/farmacología , Trementina/toxicidad , Vanadatos/farmacología , Administración Oral , Animales , Inflamación/inducido químicamente , Interleucina-10/sangre , Interleucina-6/sangre , Masculino , Dicromato de Potasio/administración & dosificación , Ratas , Vanadatos/administración & dosificaciónRESUMEN
It is well documented that age-related impaired functioning of immunocompetent cells is associated with an increase in the rates of chronic inflammatory diseases. Recently, an ability of melatonin to modulate inflammatory processes by regulating leucocyte recruitment has been demonstrated. However, to date, no studies have attempted to determine the impact of melatonin on the expression of CD62L by lymphocytes. CD62L, also known as L-selectin, is required for the entry of lymphocytes into secondary lymphoid organs, sites of tumor growth and chronic inflammation through high endothelial venules. Here, we investigated the effect of melatonin at physiological concentrations on the expression of CD62L by T and NK cells in vivo and in vitro. We demonstrated that NK and CD3+ T cells obtained from the spleen of aged mice were characterized by decreased expression of CD62L compared to young mice. Melatonin administration up-regulated the levels of surface CD62L on NK and T cell populations in aged mice under non-inflammatory conditions and on CD8+ T cells in aged mice with chronic inflammation. Pre-incubation with melatonin prevented the reduction in CD62L expression by CD8+ T cells induced by the co-cultivation of peripheral blood mononuclear cells with human pancreatic adenocarcinoma cell line (MiaPaCa-2). The obtained results suggest that melatonin can modulate lymphocyte homing into lymph nodes and sites of chronic inflammation and, therefore, can stimulate immune responses in chronic inflammatory conditions associated with aging.
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Linfocitos T CD8-positivos/fisiología , Inflamación/inmunología , Células Asesinas Naturales/fisiología , Selectina L/metabolismo , Melatonina/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/microbiología , Envejecimiento , Animales , Humanos , Inflamación/tratamiento farmacológico , Selectina L/genética , Activación de Linfocitos , Ratones , Ratones Endogámicos , Neoplasias Pancreáticas/patología , Células Tumorales Cultivadas , Regulación hacia Arriba , Neoplasias PancreáticasRESUMEN
Recent data have demonstrated that chronic inflammation is a crucial component of tumor initiation and progression. We previously reported that immature myeloid-derived suppressor cells (MDSCs) with immunosuppressive activity toward effector T cells were expanded in experimental chronic inflammation. We hypothesized that elevated levels of MDSCs, induced by chronic inflammation, may contribute to the progression of tumor growth. Using the Ehrlich carcinoma animal model, we found increased tumor growth in mice with chronic adjuvant arthritis, which was accompanied by a persistent increase in the proportion of splenic monocytic and granulocytic MDSCs expressing CD62L (L-selectin), when compared to tumor mice without adjuvant arthritis. Depletion of inflammation-induced MDSCs resulted in decreased tumor growth. In vitro studies demonstrated that increased expression of CD62L by MDSCs was mediated by TNFα, elevated concentrations of which were found in tumor mice subjected to chronic inflammation. Moreover, the addition of exogenous TNFα markedly enhanced the suppressive activity of bone marrow-derived MDSCs, as revealed by the ability to impair the proliferation of CD8+ T cells in vitro. This study provides evidence that chronic inflammation may promote tumor growth via induction of CD62L expression by MDSCs that can facilitate their migration to tumor and lymph nodes and modulation of their suppressor activity.
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Artritis Experimental/complicaciones , Inflamación/complicaciones , Selectina L/metabolismo , Células Supresoras de Origen Mieloide/metabolismo , Carga Tumoral , Animales , Movimiento Celular , Enfermedad Crónica , Ratones , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
BACKGROUND: Regulatory T cells (Tregs) play a major role in tumor escape from immunosurveillance by suppressing effector cells. The number of Tregs is increased in tumor sites and peripheral blood of breast cancer patients. However, the data regarding phenotypic and functional heterogeneity of Treg subpopulations in breast cancer are limited. The present study aimed to investigate the number and suppressive potential of Tregs that possess natural naïve-(N nTregs), effector/memory-like (EM nTregs), and Tr1-like phenotypes in breast cancer patients and healthy women. METHODS: The study included 10 HW and 17 primary breast cancer patients. Numbers of CD4+CD25+FoxP3+CD45RA+ N nTregs, CD4+CD25+FoxP3+CD45RA- EM nTregs, and CD4+IL-4-IL-10+ Tr1 subsets and the expression of CTLA-4, CD39, GITR, LAP, and IL-35 by these Treg subsets were measured in freshly obtained peripheral blood by flow cytometry. RESULTS: Herein, we demonstrate that the percentages of N nTregs, EM nTregs, CD25+ and FoxP3+ Tr1 cells are elevated in the peripheral blood of breast cancer patients, but do not correlate with cancer stages. Nevertheless, the frequency of CD25+ Tr1 cells was associated with nodal involvement, while the number of EM nTregs correlated with clinical outcome. The expression of CTLA-4 and IL-35 by all assessed Treg subsets was increased throughout all tumor stages (I-III). CONCLUSIONS: Collectively, the current study shows phenotypic alterations in suppressive receptors of Treg subsets, suggesting that breast cancer patients have increased activity of N nTregs, EM nTregs and Tr1 cells; and EM nTregs and CD25+ Tr1 cells represent prospective markers for assessing disease prognosis.
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Neoplasias de la Mama/inmunología , Subgrupos de Linfocitos T/fisiología , Linfocitos T Reguladores/fisiología , Adulto , Anciano , Apirasa/análisis , Antígeno CTLA-4/análisis , Femenino , Factores de Transcripción Forkhead/análisis , Humanos , Subunidad alfa del Receptor de Interleucina-2/análisis , Interleucinas/análisis , Persona de Mediana EdadRESUMEN
Failure of antitumor immunity in cancer was shown to be mediated by myeloid-derived suppressor cells (MDSCs), which are considered to be one of the key factors contributing to the development of malignant diseases. Therefore, the development of pharmacological approaches to effectively eliminate MDSCs in organisms carrying growing tumors is a promising pathway for potential treatment. For this purpose we propose alpha-fetoprotein (AFP) conjugated with a cytotoxic agent as a vector molecule, specifically recognizing MDSCs. The present study was aimed at examination of this suggestion using both in vitro and in vivo approaches. MDSCs, obtained from the spleen of Ehrlich carcinoma bearing mice, selectively bound AFP labeled with fluorescein isothiocyanate. AFP conjugated to daunorubicin (AFP-DR) and DR alone showed similar in vitro cytotoxicity against the granulocytic MDSC subpopulation. The monocytic MDSC subpopulation was resistant to treatment with DR, whereas it was completely depleted in the presence of AFP-DR. Treatment of mice bearing Ehrlich carcinoma with AFP-DR resulted in reduced numbers of splenic MDSCs, normalization of NK cell levels, and inhibition of tumor growth. The obtained results demonstrate that cytotoxic conjugates based on AFP are promising anticancer drugs, which, in addition to the direct effect on tumor cells expressing receptors to AFP, may contribute to elimination of MDSCs.
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Antineoplásicos/uso terapéutico , Carcinoma de Ehrlich/tratamiento farmacológico , Daunorrubicina/uso terapéutico , Células Supresoras de Origen Mieloide/efectos de los fármacos , Bazo/patología , Animales , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Daunorrubicina/química , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos , Monocitos/patología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/patología , alfa-Fetoproteínas/químicaRESUMEN
Increased serum concentrations of tumor necrosis factor α (TNFα) and transforming growth factor ß-1 (TGFß-1) in the blood of patients with pancreatic cancer (PC) have previously been demonstrated. In addition, exogenous exposure to these cytokines promotes various cancer cell invasive and cancer stem cell (CSC) phenotypes. However, their importance in pancreatic CSCs remains elusive. In the present study, the effects of TNFα and TGFß-1 on the human PC cell line MiaPaCa-2 were examined. Using flow cytometry, it was revealed that TNFα and TGFß-1 synergistically increase cluster of differentiation (CD) 44v6, CD133 and ATP-binding cassette transporter G2 (ABCG2) expressing populations in adherent tumor cell culture conditions. Furthermore, a similar trend was observed in cells pretreated with these cytokines grown in sphere forming culture conditions. Similar to previous studies, TNFα treatment increased the proportion of epidermal growth factor receptor (EGFR) expressing cells in adherent culture, and this data was further supported by the results of the sphere formation assay, in which the subculture with a high proportion of EGFR expressing cells exhibited the most efficient sphere forming ability. However, the proportion of vascular endothelial growth factor receptor 1 (VEGFR1) expressing cells did not increase upon treatment with these cytokines individually or in combination. This data was subsequently supported by the results of the wound healing assay in which cytokine treatment did not increase the migration of cells. The MTT cell proliferation and cytotoxicity assay revealed that TNFα + TGFß-1 treatment significantly increased cell proliferation and daunorubicin resistance, but not gemcitabine resistance. In conclusion, the data of the current study provide a mechanistic association between TNFα, TGFß-1 and the CSC properties of MiaPaCa-2 cells. In addition, it suggests that targeting TNFα and TGFß-1 is beneficial for improving the therapeutic efficacy of treatments for patients with PC.
RESUMEN
OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) are important negative regulators of immune processes in cancer and other pathological conditions. We suggested that MDSCs play a key role in pathogenesis of chronic inflammation, which precedes and, to a certain extent, induces carcinogenesis. The present study aimed at investigation of MDSCs arising during chronic inflammation and light-at-night (LN)-induced stress, which is shown to accelerate chronic diseases. SUBJECTS: 67 CD-1 mice and in vitro MDSC cultures. TREATMENT: Adjuvant arthritis was induced by a subdermal injection of complete Freund's adjuvant. LN was induced by illumination of 750 lx at night. METHODS: Flow cytometry for evaluation of cell phenotypes and MTT standard test for cell proliferation were used. RESULTS: Increased levels of splenic CD11b+Ly6Ghigh and CD11b+CD49d+ myeloid cells possessing suppressive potential in mice with adjuvant arthritis are shown. LN amplifies the process of CD11b+Ly6Ghigh expansion in mice with adjuvant arthritis. Expression of CD62L and CD195 is elevated on the myeloid cells during exposure to LN. CONCLUSIONS: Our study raises the possibility that CD11b+Ly6Ghigh and CD11b+CD49d+ MDSCs play an important role in the induction of immunosuppressive environment typical for chronic inflammation. Also, LN can affect immune responses during chronic inflammation through recruitment of MDSCs from the bone marrow.
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Antígenos Ly/inmunología , Artritis Experimental/inmunología , Antígeno CD11b/inmunología , Integrina alfa4/inmunología , Células Mieloides/inmunología , Estrés Fisiológico/inmunología , Animales , Artritis Experimental/sangre , Células Cultivadas , Ritmo Circadiano , Citocinas/sangre , Luz , Masculino , RatonesRESUMEN
Human natural killer (NK) cells are not only professional cytotoxic cells integrated into effector branch of innate immunity, but they are also regulatory cells, managing different immune processes. Immunoregulatory NK cells, expressing HLA-G and IL-10, have been generated in vitro from human hematopoietic progenitors and found in vivo among decidual NK cells of pregnant women. Human peripheral blood NK cells have been shown to acquire suppressive properties after HLA-G uptake during trogocytosis. Moreover, it has been shown that circulating NK cells contain a trace amount of cells producing TGF-ß and IL-10, which exert a suppressive influence upon innate and adaptive immunity. In this study, we report on a minor subset of peripheral blood HLA-G(+) NK cells possessing suppressive activity toward effector functions of NK cells. Further we demonstrate an increased number of circulating HLA-G(+), IL-10(+), and TGF-ß(+) NK cells in breast cancer patients which might impair efficiency of anti-tumor immunity.
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Neoplasias de la Mama/inmunología , Antígenos HLA-G/inmunología , Interleucina-10/inmunología , Células Asesinas Naturales/inmunología , Factor de Crecimiento Transformador beta/inmunología , Adulto , Anciano , Citotoxicidad Inmunológica/inmunología , Femenino , Humanos , Interleucina-10/biosíntesis , Masculino , Persona de Mediana Edad , Factor de Crecimiento Transformador beta/biosíntesis , Células Tumorales Cultivadas , Adulto JovenRESUMEN
According to a new paradigm of carcinogenesis, a tumor arises not from transformed cell, but only from tumor initiating cells called cancer stem cells (CSCs), which can originate from tissue stem cells. CSC are resistant to conventional therapy and after treatment form new tumors and give rise to metastases. Only natural killer (NK) cells are capable of lysing CSCs, but within different tumor types these cells experience a condition known as "split anergy", whereby the NK cells lose the ability to kill CSCs and being to produce cytokines. As a result, uncontrolled tumor growth arises and tumor stroma accumulates anergic NK cells. We hypothesize that anergic tumor infiltrating NK (TINK) cells transmit their property to naïve NK cells by infecting" them with a state of "split anergy" in a similar manner as T conventional cells are transformed into T regulatory cells during the process of "infectious tolerance". Anergic TINK cells egress from the tumor stroma via the lymphatic system, where they reach regional lymph nodes and transmit their properties to naïve NK cells, which in turn become anergic toward CSCs and lose immunosurveillance functions. The mechanisms proposed for this hypothesis and the methodological approaches for confirming the idea are presented in this issue.
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Neoplasias de la Mama/inmunología , Células Asesinas Naturales/citología , Células Madre Neoplásicas/citología , Animales , Neoplasias de la Mama/patología , Movimiento Celular , Pulpa Dental/citología , Células Madre Embrionarias/citología , Femenino , Humanos , Tolerancia Inmunológica , Sistema Linfático/fisiología , Ratones , Modelos Biológicos , Recurrencia , Células Madre/citologíaRESUMEN
Resolution of a variety of acute bacterial and parasitic infections critically relies on the stimulation of myelopoiesis leading in cases to extramedullary hematopoiesis. Here, we report the isolation of the earliest myeloid-restricted progenitors in acute infection with the rodent malaria parasite, Plasmodium chabaudi. The rapid disappearance of these infection-induced myeloid progenitors from the bone marrow (BM) equated with contraction of the functional myeloid potential in that organ. The loss of BM myelopoiesis was not affected by the complete genetic inactivation of toll-like receptor signaling. De-activation of IFN-γ signaling completely abrogated the contraction of BM myeloid progenitors. Radiation chimeras of Ifngr1-null and control BM revealed that IFN-γ signaling in an irradiation-resistant stromal compartment was crucial for the loss of early myeloid progenitors. Systemic IFN-γ triggered the secretion of C-C motif ligand chemokines CCL2 and CCL7 leading to the egress of early, myeloid-committed progenitors from the bone marrow mediated by their common receptor CCR2. The mobilization of myeloid progenitors initiated extramedullary myelopoiesis in the spleen in a CCR2-dependent manner resulting in augmented myelopoiesis during acute malaria. Consistent with the lack of splenic myelopoiesis in the absence of CCR2 we observed a significant persistence of parasitemia in malaria infected CCR2-deficient hosts. Our findings reveal how the activated immune system mobilizes early myeloid progenitors out of the BM thereby transiently establishing myelopoiesis in the spleen in order to contain and resolve the infection locally.
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Quimiocina CCL2/inmunología , Quimiocina CCL7/inmunología , Hematopoyesis Extramedular/inmunología , Interferón gamma/inmunología , Malaria/inmunología , Células Progenitoras Mieloides/inmunología , Mielopoyesis/inmunología , Plasmodium chabaudi/inmunología , Animales , Quimiocina CCL2/genética , Quimiocina CCL7/genética , Interferón gamma/genética , Malaria/genética , Ratones , Ratones Noqueados , Receptores CCR2/genética , Receptores CCR2/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunología , Bazo/inmunología , Receptores Toll-Like/genética , Receptores Toll-Like/inmunologíaRESUMEN
T cell development constitutes a multistage process allowing the dissection of events resulting in cellular commitment and functional specification in a specialized microenvironment. This process is guided by the appropriate expression of regulatory genetic factors like transcriptional activators or repressors which are, in part, dependent on instructive signals of the microenvironment. To date, it remains unclear whether exactly the same genetic mechanism acts in adult compared to fetal T cell development. In order to directly compare T cell commitment during adult and fetal differentiation, we isolated subsequent stages of intrathymic subpopulations starting with early canonical T cell progenitors up to irreversibly committed T cell precursors. The genome-wide analysis revealed several distinct gene clusters with a specific pattern of gene regulation for each subset. The largest cluster contained genes upregulated after transition through the most primitive pool into the next transitory population with a consistently elevated expression of elements associated with ongoing T cell fate specification, like Gata3 and Tcf7, in fetal progenitors. Furthermore, adult and fetal T cell progenitors occupied distinct "transcriptional territories" revealing a precise land map of the progression to final T cell commitment operating in different developmental windows. The presence and/or elevated expression of elements associated with an ongoing establishment of a T cell signature in the most primitive fetal subset is highly suggestive for an extrathymic initiation of T cell specification and underlines the fundamental differences in fetal versus adult lymphopoiesis.
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Diferenciación Celular/genética , Linaje de la Célula/genética , Feto , Perfilación de la Expresión Génica , Linfocitos T/fisiología , Timocitos/fisiología , Animales , Femenino , Regulación de la Expresión Génica , Células Madre Hematopoyéticas/fisiología , Linfopoyesis , Ratones , Ratones Endogámicos C57BL , Análisis por MicromatricesRESUMEN
Bone morphogenetic protein (BMP) signalling regulates lymphopoiesis in bone marrow and thymus via the interaction of haemato-lymphoid progenitors with the stroma microenvironment. Despite increasing functional evidence for the role of BMP signalling in lymphopoiesis, little is known of the spatial distribution of BMP/BMP antagonists in the thymus and of how BMP signals exert specific functions in developing lymphocytes. We analysed expression of BMP/BMP antagonists in the thymus and bone marrow and determined the topology of BMP/BMP antagonist expression using lacZ reporter mice. Bmp4, Bmp7, Gremlin and Twisted gastrulation (Twsg1) are all expressed in the thymus and expression was clearly different for each gene investigated. Expression was seen both in cortical and medullary regions suggesting that BMP signals regulate all stages of T-cell development. Two genes in particular, Bmp7 and Twsg1, were dynamically expressed in developing T and B lymphocytes. Their conditional ablation in all haematopoietic cells surprisingly did not affect the steady state of B-cell and T-cell development. This indicates that both lymphoid cell-derived BMP7 and TWSG1 are dispensable for normal lymphopoiesis and that bone-marrow stroma-derived TWSG1 is responsible for the lymphoid defects observed in Twsg1 null mice. In summary our data demonstrate a complex network of lymphoid and stroma derived BMP signals involved in the orchestration of lymphopoiesis in both bone marrow and thymus.
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Proteínas Morfogenéticas Óseas/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Linfocitos/metabolismo , Proteínas/genética , Nicho de Células Madre/genética , Células Madre/metabolismo , Animales , Médula Ósea/metabolismo , Proteína Morfogenética Ósea 4/genética , Proteína Morfogenética Ósea 4/metabolismo , Proteína Morfogenética Ósea 7/genética , Proteína Morfogenética Ósea 7/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Citocinas , Citometría de Flujo , Perfilación de la Expresión Génica , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Linfopoyesis/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteínas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Timo/metabolismo , Factores de Tiempo , beta-Galactosidasa/genética , beta-Galactosidasa/metabolismoRESUMEN
Although the relationship between hematopoietic stem cells and progenitor populations has been investigated extensively under steady-state conditions, the dynamic response of the hematopoietic compartment during acute infection is largely unknown. Here we show that after infection of mice with Plasmodium chabaudi, a c-Kit(hi) progenitor subset positive for interleukin 7 receptor-alpha (IL-7Ralpha) emerged that had both lymphoid and myeloid potential in vitro. After being transferred into uninfected alymphoid or malaria-infected hosts, IL-7Ralpha(+)c-Kit(hi) progenitors generated mainly myeloid cells that contributed to the clearance of infected erythrocytes in infected hosts. The generation of these infection-induced progenitors was critically dependent on interferon-gamma (IFN-gamma) signaling in hematopoietic progenitors. Thus, IFN-gamma is a key modulator of hematopoiesis and innate and adaptive immunity during acute malaria infection.