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1.
Sci Immunol ; 7(78): eadd3330, 2022 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-36525505

RESUMEN

Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.


Asunto(s)
Histiocitosis de Células de Langerhans , Neoplasias , Humanos , Linaje de la Célula , Histiocitosis de Células de Langerhans/metabolismo , Histiocitosis de Células de Langerhans/patología , Diferenciación Celular , Monocitos/metabolismo
2.
Sci Rep ; 12(1): 1911, 2022 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-35115587

RESUMEN

Many critical advances in research utilize techniques that combine high-resolution with high-content characterization at the single cell level. We introduce the MICS (MACSima Imaging Cyclic Staining) technology, which enables the immunofluorescent imaging of hundreds of protein targets across a single specimen at subcellular resolution. MICS is based on cycles of staining, imaging, and erasure, using photobleaching of fluorescent labels of recombinant antibodies (REAfinity Antibodies), or release of antibodies (REAlease Antibodies) or their labels (REAdye_lease Antibodies). Multimarker analysis can identify potential targets for immune therapy against solid tumors. With MICS we analysed human glioblastoma, ovarian and pancreatic carcinoma, and 16 healthy tissues, identifying the pair EPCAM/THY1 as a potential target for chimeric antigen receptor (CAR) T cell therapy for ovarian carcinoma. Using an Adapter CAR T cell approach, we show selective killing of cells only if both markers are expressed. MICS represents a new high-content microscopy methodology widely applicable for personalized medicine.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Molécula de Adhesión Celular Epitelial/metabolismo , Técnica del Anticuerpo Fluorescente , Inmunoterapia Adoptiva , Neoplasias/metabolismo , Neoplasias/terapia , Fotoblanqueo , Análisis de la Célula Individual , Antígenos Thy-1/metabolismo , Muerte Celular , Citotoxicidad Inmunológica , Ensayos Analíticos de Alto Rendimiento , Humanos , Neoplasias/inmunología , Neoplasias/patología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/trasplante
3.
Immunity ; 50(2): 446-461.e9, 2019 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-30709742

RESUMEN

Production of interleukin-17 (IL-17) and IL-22 by T helper 17 (Th17) cells and group 3 innate lymphoid cells (ILC3s) in response to the gut microbiota ensures maintenance of intestinal barrier function. Here, we examined the mechanisms whereby the immune system detects microbiota in the steady state. A Syk-kinase-coupled signaling pathway in dendritic cells (DCs) was critical for commensal-dependent production of IL-17 and IL-22 by CD4+ T cells. The Syk-coupled C-type lectin receptor Mincle detected mucosal-resident commensals in the Peyer's patches (PPs), triggered IL-6 and IL-23p19 expression, and thereby regulated function of intestinal Th17- and IL-17-secreting ILCs. Mice deficient in Mincle or with selective depletion of Syk in CD11c+ cells had impaired production of intestinal RegIIIγ and IgA and increased systemic translocation of gut microbiota. Consequently, Mincle deficiency led to liver inflammation and deregulated lipid metabolism. Thus, sensing of commensals by Mincle and Syk signaling in CD11c+ cells reinforces intestinal immune barrier and promotes host-microbiota mutualism, preventing systemic inflammation.


Asunto(s)
Células Dendríticas/inmunología , Microbioma Gastrointestinal/inmunología , Interleucina-17/inmunología , Interleucinas/inmunología , Lectinas Tipo C/inmunología , Proteínas de la Membrana/inmunología , Quinasa Syk/inmunología , Animales , Células Dendríticas/metabolismo , Microbioma Gastrointestinal/fisiología , Humanos , Interleucina-17/metabolismo , Interleucinas/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ganglios Linfáticos Agregados/inmunología , Ganglios Linfáticos Agregados/metabolismo , Ganglios Linfáticos Agregados/microbiología , Transducción de Señal/inmunología , Quinasa Syk/genética , Quinasa Syk/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Interleucina-22
4.
Cell Adh Migr ; 9(3): 247-53, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25495756

RESUMEN

Neuron migration defects are an important aspect of human neuropathies. The underlying molecular mechanisms of such migration defects are largely unknown. Actin dynamics has been recognized as an important determinant of neuronal migration, and we recently found that the actin-binding protein profilin1 is relevant for radial migration of cerebellar granule neurons (CGN). As the exploited brain-specific mutants lacked profilin1 in both neurons and glial cells, it remained unknown whether profilin1 activity in CGN is relevant for CGN migration in vivo. To test this, we capitalized on a transgenic mouse line that expresses a tamoxifen-inducible Cre variant in CGN, but no other cerebellar cell type. In these profilin1 mutants, the cell density was elevated in the molecular layer, and ectopic CGN occurred. Moreover, 5-bromo-2'-deoxyuridine tracing experiments revealed impaired CGN radial migration. Hence, our data demonstrate the cell autonomous role of profilin1 activity in CGN for radial migration.


Asunto(s)
Movimiento Celular , Cerebelo/citología , Neuronas/citología , Neuronas/metabolismo , Profilinas/metabolismo , Actinas/metabolismo , Animales , Ratones , Ratones Transgénicos , Neurogénesis , Neuroglía/citología
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