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1.
Front Immunol ; 14: 1105103, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36969261

RESUMEN

Introduction: MISTRG mice have been genetically modified to allow development of a human myeloid compartment from engrafted human CD34+ haemopoietic stem cells, making them particularly suited to study the human innate immune system in vivo. Here, we characterized the human neutrophil population in these mice to establish a model that can be used to study the biology and contribution in immune processes of these cells in vivo. Methods and results: We could isolate human bone marrow neutrophils from humanized MISTRG mice and confirmed that all neutrophil maturation stages from promyelocytes (CD11b-CD16-) to end-stage segmented cells (CD11b+CD16+) were present. We documented that these cells possessed normal functional properties, including degranulation, reactive oxygen species production, adhesion, and antibody-dependent cellular cytotoxicity towards antibody-opsonized tumor cells ex vivo. The acquisition of functional capacities positively correlated with the maturation state of the cell. We found that human neutrophils were retained in the bone marrow of humanized MISTRG mice during steady state. However, the mature segmented CD11b+CD16+ human neutrophils were released from the bone marrow in response to two well-established neutrophil-mobilizing agents (i.e., G-CSF and/or CXCR4 antagonist Plerixafor). Moreover, the neutrophil population in the humanized MISTRG mice actively reacted to thioglycolate-induced peritonitis and could infiltrate implanted human tumors, as shown by flow cytometry and fluorescent microscopy. Discussion: These results show that functional human neutrophils are generated and can be studied in vivo using the humanized MISTRG mice, providing a model to study the various functions of neutrophils in inflammation and in tumors.


Asunto(s)
Compuestos Heterocíclicos , Neutrófilos , Humanos , Ratones , Animales , Movilización de Célula Madre Hematopoyética , Médula Ósea , Inmunidad
2.
Cells ; 11(1)2021 12 24.
Artículo en Inglés | MEDLINE | ID: mdl-35011617

RESUMEN

Apart from controlling hematopoiesis, the bone marrow (BM) also serves as a secondary lymphoid organ, as it can induce naïve T cell priming by resident dendritic cells (DC). When analyzing DCs in murine BM, we uncovered that they are localized around sinusoids, can (cross)-present antigens, become activated upon intravenous LPS-injection, and for the most part belong to the cDC2 subtype which is associated with Th2/Th17 immunity. Gene-expression profiling revealed that BM-resident DCs are enriched for several c-type lectins, including Dectin-1, which can bind beta-glucans expressed on fungi and yeast. Indeed, DCs in BM were much more efficient in phagocytosis of both yeast-derived zymosan-particles and Aspergillus conidiae than their splenic counterparts, which was highly dependent on Dectin-1. DCs in human BM could also phagocytose zymosan, which was dependent on ß1-integrins. Moreover, zymosan-stimulated BM-resident DCs enhanced the differentiation of hematopoietic stem and progenitor cells towards neutrophils, while also boosting the maintenance of these progenitors. Our findings signify an important role for BM DCs as translators between infection and hematopoiesis, particularly in anti-fungal immunity. The ability of BM-resident DCs to boost neutrophil formation is relevant from a clinical perspective and contributes to our understanding of the increased susceptibility for fungal infections following BM damage.


Asunto(s)
Antígenos Fúngicos/inmunología , Células de la Médula Ósea/inmunología , Células Dendríticas/inmunología , Neutrófilos/inmunología , Anciano , Anciano de 80 o más Años , Animales , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos/metabolismo , Humanos , Inflamación/patología , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Antígeno de Macrófago-1/metabolismo , Ratones Endogámicos C57BL , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Zimosan/metabolismo
3.
Immunol Lett ; 222: 73-79, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32259529

RESUMEN

Follicular helper CD4+ T-cells (Tfh) control humoral immunity by driving affinity maturation and isotype-switching of activated B-cells. Tfh localize within B-cell follicles and, upon encounter with cognate antigen, drive B-cell selection in germinal centers (GCs) as GC-Tfh. Tfh functionality is controlled by Foxp3-expressing Tfh, which are known as regulatory T follicular cells (Tfr). Thus far, it remains unclear which factors determine the balance between these functionally opposing follicular T-cell subsets. Here, we demonstrate in human and mouse that Tfh and GC-Tfh, as well as their regulatory counterparts, express glucocorticoid-induced TNF receptor related protein (GITR) on their surface. This costimulatory molecule not only helps to identify follicular T-cell subsets, but also increases the ratio of Tfh vs. Tfr, both within and outside the GC. Correspondingly, GITR triggering increases the number of IL-21 producing CD4+ T-cells, which also produce more IFN-γ and IL-10. The latter are known switch factors for IgG2c and IgG1, respectively, which corresponds to a concomitant increase in IgG2c and IgG1 production upon GITR-mediated costimulation. These results demonstrate that GITR can skew the functional balance between Tfh and Tfr, which offers new therapeutic possibilities in steering humoral immunity.


Asunto(s)
Proteína Relacionada con TNFR Inducida por Glucocorticoide/genética , Inmunidad Humoral , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biomarcadores , Citocinas/metabolismo , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Regulación de la Expresión Génica , Centro Germinal/inmunología , Centro Germinal/metabolismo , Proteína Relacionada con TNFR Inducida por Glucocorticoide/metabolismo , Humanos , Cambio de Clase de Inmunoglobulina/genética , Masculino , Ratones
4.
Eur J Immunol ; 49(6): 853-872, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30891737

RESUMEN

BM has been put forward as a major reservoir for memory CD8+  T cells. In order to fulfill that function, BM should "store" memory CD8+ T cells, which in biological terms would require these "stored" memory cells to be in disequilibrium with the circulatory pool. This issue is a matter of ongoing debate. Here, we unequivocally demonstrate that murine and human BM harbors a population of tissue-resident memory CD8+ T (TRM ) cells. These cells develop against various pathogens, independently of BM infection or local antigen recognition. BM CD8+ TRM cells share a transcriptional program with resident lymphoid cells in other tissues; they are polyfunctional cytokine producers and dependent on IL-15, Blimp-1, and Hobit. CD8+ TRM cells reside in the BM parenchyma, but are in close contact with the circulation. Moreover, this pool of resident T cells is not size-restricted and expands upon peripheral antigenic re-challenge. This works extends the role of the BM in the maintenance of CD8+ T cell memory to include the preservation of an expandable reservoir of functional, non-recirculating memory CD8+ T cells, which develop in response to a large variety of peripheral antigens.


Asunto(s)
Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Humanos , Ratones , Ratones Endogámicos C57BL
5.
Eur J Immunol ; 49(4): 576-589, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30707456

RESUMEN

The BM serves as a blood-forming organ, but also supports the maintenance and immune surveillance function of many T cells. Yet, in contrast to other organs, little is known about the molecular mechanisms that drive T-cell migration to and localization inside the BM. As BM accumulates many CXCR3-expressing memory CD8+ T cells, we tested the involvement of this chemokine receptor, but found that CXCR3 is not required for BM entry. In contrast, we could demonstrate that CXCR4, which is highly expressed on both naive and memory CD8+ T cells in BM, is critically important for homing of all CD8+ T-cell subsets to the BM in mice. Upon entry into the BM parenchyma, both naïve and memory CD8+ T cells locate close to sinusoidal vessels. Intravital imaging experiments revealed that CD8 T cells are surprisingly immobile and we found that they interact with ICAM-1+VCAM-1+BP-1+ perivascular stromal cells. These cells are the major source of CXCL12, but also express key survival factors and maintenance cytokines IL-7 and IL-15. We therefore conclude that CXCR4 is not only crucial for entry of CD8+ T cells into the BM, but also controls their subsequent localization toward BM niches that support their survival.


Asunto(s)
Médula Ósea/inmunología , Médula Ósea/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Movimiento Celular/inmunología , Microambiente Celular , Receptores CXCR4/metabolismo , Animales , Médula Ósea/irrigación sanguínea , Médula Ósea/patología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Comunicación Celular/inmunología , Microambiente Celular/genética , Microambiente Celular/inmunología , Citocinas/biosíntesis , Memoria Inmunológica , Ratones , Receptores CXCR3 , Células del Estroma/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
6.
Sci Rep ; 8(1): 15385, 2018 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-30337617

RESUMEN

In chronic kidney disease (CKD), endothelial injury, is associated with disease progression and an increased risk for cardiovascular complications. Circulating cells with vascular reparative functions are hematopoietic and also reduced in CKD. To explore the mechanistic basis behind these observations, we have investigated hematopoietic stem cell (HSC) homeostasis in a mouse model for non-progressive CKD-mineral and bone disorder with experimentally induced chronic renal failure (CRF). In mice subjected to 12 weeks of CRF, bone marrow HSC frequencies were decreased and transplantation of bone marrow cells from CRF donors showed a decrease in long-term HSC repopulation compared to controls. This loss was directly associated with a CRF-induced defect in the HSC niche affecting the cell cycle status of HSC and could not be restored by the PTH-reducing agent cinacalcet. In CRF, frequencies of quiescent (G0) HSC were decreased coinciding with an increase in hematopoietic progenitor cells (HPC) in the S-and G2-phases of cell cycle. Moreover, in CRF mice, HSC-niche supporting macrophages were decreased compared to controls concomitant to impaired B lymphopoiesis. Our data point to a permanent loss of HSC and may provide insight into the root cause of the loss of homeostatic potential in CKD.


Asunto(s)
Enfermedades de la Médula Ósea/etiología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/complicaciones , Células Madre Hematopoyéticas/patología , Nicho de Células Madre , Animales , Densidad Ósea/efectos de los fármacos , Enfermedades de la Médula Ósea/patología , Recuento de Células , Ciclo Celular/efectos de los fármacos , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/tratamiento farmacológico , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/fisiopatología , Cinacalcet/farmacología , Cinacalcet/uso terapéutico , Modelos Animales de Enfermedad , Endotelio Vascular/patología , Femenino , Homeostasis , Linfopoyesis , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Nefrectomía , Osteoblastos/patología
7.
PLoS Pathog ; 11(3): e1004675, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25738498

RESUMEN

Chronic infections are characterized by the inability to eliminate the persisting pathogen and often associated with functional impairment of virus-specific T-cell responses. Costimulation through Glucocorticoid-induced TNFR-related protein (GITR) can increase survival and function of effector T cells. Here, we report that constitutive expression of GITR-ligand (GITRL) confers protection against chronic lymphocytic choriomeningitis virus (LCMV) infection, accelerating recovery without increasing pathology. Rapid viral clearance in GITRL transgenic mice coincided with increased numbers of poly-functional, virus-specific effector CD8+ T cells that expressed more T-bet and reduced levels of the rheostat marker PD-1. GITR triggering also boosted the helper function of virus-specific CD4 T cells already early in the infection, as was evidenced by increased IL-2 and IFNγ production, and more expression of CD40L and T-bet. Importantly, CD4-depletion experiments revealed that the expanded pool of virus-specific effector CD8 T cells and the ensuing viral clearance in LCMV-infected GITRL tg mice was entirely dependent on CD4 T cells. We found no major differences for NK cell and regulatory T cell responses, whereas the humoral response to the virus was increased in GITRL tg mice, but only in the late phase of the infection when the virus was almost eradicated. Based on these findings, we conclude that enhanced GITR-triggering mediates its protective, anti-viral effect on the CD8 T cell compartment by boosting CD4 T cell help. As such, increasing costimulation through GITR may be an attractive strategy to increase anti-viral CTL responses without exacerbating pathology, in particular to persistent viruses such as HIV and HCV.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Proteína Relacionada con TNFR Inducida por Glucocorticoide/inmunología , Inmunidad Celular , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Ligando de CD40/genética , Ligando de CD40/inmunología , Linfocitos T CD8-positivos/patología , Enfermedad Crónica , Proteína Relacionada con TNFR Inducida por Glucocorticoide/genética , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-2/genética , Interleucina-2/inmunología , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/patología , Ratones , Ratones Transgénicos , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunología , Linfocitos T Colaboradores-Inductores/patología
8.
Kidney Int ; 81(7): 651-61, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22237752

RESUMEN

Syndecan-1, a heparan sulfate proteoglycan, has an important role in wound healing by binding several growth factors and cytokines. As these processes are also crucial in damage and repair after renal transplantation, we examined syndecan-1 expression in human control kidney tissue, renal allograft protocol biopsies, renal allograft biopsies taken at indication, and non-transplant interstitial fibrosis. Syndecan-1 expression was increased in tubular epithelial cells in renal allograft biopsies compared with control. Increased epithelial syndecan-1 in allografts correlated with low proteinuria and serum creatinine, less interstitial inflammation, less tubular atrophy, and prolonged allograft survival. Knockdown of syndecan-1 in human tubular epithelial cells in vitro reduced cell proliferation. Selective binding of growth factors suggests that syndecan-1 may promote epithelial restoration. Bilateral renal ischemia/reperfusion in syndecan-1-deficient mice resulted in increased initial renal failure and tubular injury compared with wild-type mice. Macrophage and myofibroblast numbers, tubular damage, and plasma urea levels were increased, and tubular proliferation reduced in the kidneys of syndecan-1 deficient compared with wild-type mice 14 days following injury. Hence syndecan-1 promotes tubular survival and repair in murine ischemia/reperfusion injury and correlates with functional improvement in human renal allograft transplantation.


Asunto(s)
Trasplante de Riñón/fisiología , Túbulos Renales/fisiología , Daño por Reperfusión/fisiopatología , Sindecano-1/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Secuencia de Bases , Línea Celular , Células Epiteliales/fisiología , Femenino , Fibrosis , Técnicas de Silenciamiento del Gen , Factor de Crecimiento Similar a EGF de Unión a Heparina , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Riñón/lesiones , Riñón/patología , Riñón/fisiopatología , Túbulos Renales/patología , Túbulos Renales/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , ARN Interferente Pequeño/genética , Sindecano-1/antagonistas & inhibidores , Sindecano-1/deficiencia , Sindecano-1/genética , Trasplante Homólogo , Adulto Joven
9.
J Surg Oncol ; 102(6): 640-8, 2010 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-20677220

RESUMEN

BACKGROUND AND OBJECTIVES: Surgical procedures can cause tumor cells to disseminate into the circulatory system. Although this spread of metastatic cells will be limited by immune activity, immunosuppression tends to be the main effect resulting from surgery. The objective of this study is to assess hormonal and immunological changes induced by breast cancer surgery. METHODS: Endocrine and immune responses to surgery were determined in 27 breast cancer patients. Blood samples were taken at 6 days and 1 day before surgery and 2 hr, 1 day, and 5 days after surgery. Changes in endocrine function, number of leucocytes and their subpopulations, enumerative immune expression, functional activity, and cytokine levels were determined. RESULTS: Breast cancer surgery induces a pro-inflammatory response and leucocytosis. Immunosuppression is indicated by decreased HLA-DR expression, decreased NKCA, and a Th2 response. A delayed Th1 response was also found 5 days after surgery. As no cortisol level change was observed, this hormone can be excluded as the mediator of surgery-related immunomodulation in breast cancer. CONCLUSION: Although breast cancer surgery is classified as minor surgery the surgical procedure produces substantial immunomodulation.


Asunto(s)
Neoplasias de la Mama/inmunología , Neoplasias de la Mama/cirugía , Inmunomodulación , Proteína C-Reactiva/análisis , Citocinas/metabolismo , Femenino , Humanos , Hidrocortisona/análisis , Tolerancia Inmunológica , Inmunidad Celular
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