RESUMEN
Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. In the present study Irf8 enhancers were identified via chromatin profiling of dendritic cells and CRISPR/Cas9 genome editing was used to assess their roles in Irf8 regulation. An enhancer 32 kilobases (kb) downstream of the Irf8 transcriptional start site (+32-kb Irf8) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41-kb Irf8 enhancer, previously thought to be active only in plasmacytoid dendritic cells, was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41-kb Irf8 enhancer in dendritic cell progenitors is responsible for cDC1 fate specification.
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Células Dendríticas/citología , Elementos de Facilitación Genéticos/genética , Factores Reguladores del Interferón/metabolismo , Macrófagos/citología , Monocitos/citología , Animales , Sistemas CRISPR-Cas/genética , Diferenciación Celular , Linaje de la Célula , Células Dendríticas/inmunología , Regulación de la Expresión Génica , Factores Reguladores del Interferón/genética , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/metabolismo , Células Madre/citología , Células Tumorales CultivadasRESUMEN
Conventional type 1 dendritic cells (cDC1)1 are thought to perform antigen cross-presentation, which is required to prime CD8+ T cells2,3, whereas cDC2 are specialized for priming CD4+ T cells4,5. CD4+ T cells are also considered to help CD8+ T cell responses through a variety of mechanisms6-11, including a process whereby CD4+ T cells 'license' cDC1 for CD8+ T cell priming12. However, this model has not been directly tested in vivo or in the setting of help-dependent tumour rejection. Here we generated an Xcr1Cre mouse strain to evaluate the cellular interactions that mediate tumour rejection in a model requiring CD4+ and CD8+ T cells. As expected, tumour rejection required cDC1 and CD8+ T cell priming required the expression of major histocompatibility class I molecules by cDC1. Unexpectedly, early priming of CD4+ T cells against tumour-derived antigens also required cDC1, and this was not simply because they transport antigens to lymph nodes for processing by cDC2, as selective deletion of major histocompatibility class II molecules in cDC1 also prevented early CD4+ T cell priming. Furthermore, deletion of either major histocompatibility class II or CD40 in cDC1 impaired tumour rejection, consistent with a role for cognate CD4+ T cell interactions and CD40 signalling in cDC1 licensing. Finally, CD40 signalling in cDC1 was critical not only for CD8+ T cell priming, but also for initial CD4+ T cell activation. Thus, in the setting of tumour-derived antigens, cDC1 function as an autonomous platform capable of antigen processing and priming for both CD4+ and CD8+ T cells and of the direct orchestration of their cross-talk that is required for optimal anti-tumour immunity.
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Linfocitos T CD4-Positivos/inmunología , Reactividad Cruzada , Células Dendríticas/inmunología , Neoplasias/inmunología , Animales , Presentación de Antígeno/inmunología , Linfocitos T CD4-Positivos/citología , Antígenos CD40/inmunología , Antígenos CD40/metabolismo , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/citología , Células Dendríticas/metabolismo , Femenino , Antígenos de Histocompatibilidad Clase II/inmunología , Ratones , Transducción de SeñalRESUMEN
INTRODUCTION: Despite considerable interest in robotic surgery, successful incorporation of robotics into transplant programs has been challenging. Lack of a dedicated OR team with expertise in both robotics and transplant is felt to be a major barrier. This paper assesses the impact of a dedicated robotic transplant team (DART) on program growth and fellowship training at one of the largest robotic transplant programs in North America. METHODS: This is a single center, retrospective review of all robotic operations performed on the transplant surgery service from October 2017 to October 2022. DART was incorporated in February 2020 and included transplant first assists (RFAs), scrub technologists and circulating nurses who received robotic training. Robotic experience before and after DART was compared to assess its impact on program growth and training. RESULTS: Four hundred and two robotic cases were performed by five transplant surgeons: 63 pre-DART and 339 post-DART. 40% of cases were transplant-related and 59.5%, HPB. There was a significant increase in case volume (2.5-10.6 cases/month, p < .0001) and complexity (36.5% vs. 70.3% high complexity cases, p < .0001) post-DART. RFA case coverage increased from 17% to 95%, and participation of transplant fellows as primary surgeons increased from 17% to 95% post-DART period (both p < .05). Conversion rates (9.5% vs. 4.1%) and room turn-around-times (TAT) (58.4 vs. 40.3 min) were lower post-DART (p < .05). There were no emergent conversions, conversions in transplant patients, or robot-related complications in either group. CONCLUSION: OR teams with expertise in robotics and transplant surgery can accelerate growth of robotic transplant programs while maintaining patient safety.
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Procedimientos Quirúrgicos Robotizados , Robótica , Cirujanos , Humanos , Becas , QuirófanosRESUMEN
CD4+ T follicular helper (TFH) cells support germinal center (GC) reactions promoting humoral immunity. Dendritic cell (DC) diversification into genetically distinct subsets allows for specialization in promoting responses against several types of pathogens. Whether any classical DC (cDC) subset is required for humoral immunity is unknown, however. We tested several genetic models that selectively ablate distinct DC subsets in mice for their impact on splenic GC reactions. We identified a requirement for Notch2-dependent cDC2s, but not Batf3-dependent cDC1s or Klf4-dependent cDC2s, in promoting TFH and GC B cell formation in response to sheep red blood cells and inactivated Listeria monocytogenes This effect was mediated independent of Il2ra and several Notch2-dependent genes expressed in cDC2s, including Stat4 and Havcr2 Notch2 signaling during cDC2 development also substantially reduced the efficiency of cDC2s for presentation of MHC class II-restricted antigens, limiting the strength of CD4 T cell activation. Together, these results demonstrate a nonredundant role for the Notch2-dependent cDC2 subset in supporting humoral immune responses.
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Linfocitos B/inmunología , Células Dendríticas/inmunología , Eritrocitos/inmunología , Centro Germinal/inmunología , Receptor Notch2/fisiología , Bazo/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Presentación de Antígeno/inmunología , Linfocitos B/metabolismo , Diferenciación Celular , Células Cultivadas , Células Dendríticas/metabolismo , Centro Germinal/metabolismo , Inmunidad Humoral/inmunología , Factor 4 Similar a Kruppel , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ovinos , Transducción de Señal , Bazo/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
RelB is an NF-κB family transcription factor activated in the noncanonical pathway downstream of NF-κB-inducing kinase (NIK) and TNF receptor family members including lymphotoxin-ß receptor (LTßR) and CD40. Early analysis suggested that RelB is required for classical dendritic cell (cDC) development based on a severe reduction of cDCs in Relb-/- mice associated with profound myeloid expansion and perturbations in B and T cells. Subsequent analysis of radiation chimeras generated from wild-type and Relb-/- bone marrow showed that RelB exerts cell-extrinsic actions on some lineages, but it has remained unclear whether the impact of RelB on cDC development is cell-intrinsic or -extrinsic. Here, we reevaluated the role of RelB in cDC and myeloid development using a series of radiation chimeras. We found that there was no cell-intrinsic requirement for RelB for development of most cDC subsets, except for the Notch2- and LTßR-dependent subset of splenic CD4+ cDC2s. These results identify a relatively restricted role of RelB in DC development. Moreover, the myeloid expansion in Relb-/- mice resulted from hematopoietic-extrinsic actions of RelB. This result suggests that there is an unrecognized but critical role for RelB within the nonhematopoietic niche that controls normal myelopoiesis.
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Células Dendríticas/fisiología , Células Mieloides/fisiología , Factor de Transcripción ReIB/genética , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Sistema Hematopoyético/citología , Sistema Hematopoyético/metabolismo , Receptor beta de Linfotoxina/metabolismo , Linfotoxina beta/metabolismo , Ratones Endogámicos C57BL , Ratones Mutantes , Proteínas Serina-Treonina Quinasas/metabolismo , Bazo/citología , Bazo/metabolismo , Factor de Transcripción ReIB/metabolismo , Quinasa de Factor Nuclear kappa BRESUMEN
BACKGROUND: Staging laparoscopy (SL) is used to avoid resection failure and thus increase the curative resection rate. SL utilization in extra-hepatic biliary tumors (EHBT) is variable. METHODS: Data from 1090 patients with potentially resectable EHBT including gallbladder (GBC), distal (DC), and hilar (HC) subtypes were retrospectively collected from 10 academic centers (2000-2015). RESULTS: The SL utilization rate increased over time and was significantly higher in GBC than DC and HC. SL yield was 16.8% and did not differ between groups or over time. In patients undergoing attempted resection with prior SL, the curative resection rate did not differ between subtypes. In patients undergoing attempted resection without prior SL, the curative resection rate was less in GBC compared with DC or HC. After matching cohorts by inverse probability weighting, prior SL was associated with curative resection in GBC only (odds ratio [OR], 2.41, 95% CI, 1.36-4.27). On multivariable regression analysis, elevated carbohydrate antigen 19-9 (CA 19-9), low serum albumin, and GBC were strong predictors of distant disease on SL. After categorizing patients undergoing SL into low, intermediate, and high-risk groups based on these parameters, SL yield improved progressively from 10.0% to 19.6% to 52.6%. CONCLUSIONS: We recommend routine SL for patients with GBC, particularly with elevated CA19-9 level and/or decreased serum albumin.
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Neoplasias del Sistema Biliar/patología , Neoplasias de la Vesícula Biliar/patología , Tumor de Klatskin/patología , Laparoscopía/métodos , Neoplasias Hepáticas/patología , Anciano , Neoplasias del Sistema Biliar/cirugía , Femenino , Estudios de Seguimiento , Neoplasias de la Vesícula Biliar/cirugía , Humanos , Tumor de Klatskin/cirugía , Neoplasias Hepáticas/cirugía , Masculino , Estadificación de Neoplasias , Curva ROC , Estudios Retrospectivos , Factores de TiempoRESUMEN
BACKGROUND: Curative-intent treatment for localized hilar cholangiocarcinoma (HC) requires surgical resection. However, the effect of adjuvant therapy (AT) on survival is unclear. We analyzed the impact of AT on overall (OS) and recurrence free survival (RFS) in patients undergoing curative resection. METHODS: We reviewed patients with resected HC between 2000 and 2015 from the ten institutions participating in the U.S. Extrahepatic Biliary Malignancy Consortium. We analyzed the impact of AT on RFS and OS. The probability of RFS and OS were calculated in the method of Kaplan and Meier and analyzed using multivariate Cox regression analysis. RESULTS: A total of 249 patients underwent curative resection for HC. Patients who received AT and those who did not had similar demographic and preoperative features. In a multivariate Cox regression analysis, AT conferred a significant protective effect on OS (HR 0.58, P = 0.013), and this was maintained in a propensity matched analysis (HR 0.66, P = 0.033). The protective effect of AT remained significant when node negative patients were excluded (HR 0.28, P = 0.001), while it disappeared (HR 0.76, P = 0.260) when node positive patients were excluded. CONCLUSIONS: AT should be strongly considered after curative-intent resection for HC, particularly in patients with node positive disease.
Asunto(s)
Neoplasias de los Conductos Biliares/terapia , Colangiocarcinoma/terapia , Anciano , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/cirugía , Quimioradioterapia Adyuvante , Quimioterapia Adyuvante , Colangiocarcinoma/patología , Colangiocarcinoma/cirugía , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Surgical resection is the cornerstone of curative-intent therapy for patients with hilar cholangiocarcinoma (HC). The role of vascular resection (VR) in the treatment of HC in western centres is not well defined. METHODS: Utilizing data from the U.S. Extrahepatic Biliary Malignancy Consortium, patients were grouped into those who underwent resection for HC based on VR status: no VR, portal vein resection (PVR), or hepatic artery resection (HAR). Perioperative and long-term survival outcomes were analyzed. RESULTS: Between 1998 and 2015, 201 patients underwent resection for HC, of which 31 (15%) underwent VR: 19 patients (9%) underwent PVR alone and 12 patients (6%) underwent HAR either with (n = 2) or without PVR (n = 10). Patients selected for VR tended to be younger with higher stage disease. Rates of postoperative complications and 30-day mortality were similar when stratified by vascular resection status. On multivariate analysis, receipt of PVR or HAR did not significantly affect OS or RFS. CONCLUSION: In a modern, multi-institutional cohort of patients undergoing curative-intent resection for HC, VR appears to be a safe procedure in a highly selected subset, although long-term survival outcomes appear equivalent. VR should be considered only in select patients based on tumor and patient characteristics.
Asunto(s)
Neoplasias de los Conductos Biliares/cirugía , Colecistectomía , Hepatectomía , Arteria Hepática/cirugía , Tumor de Klatskin/cirugía , Pancreaticoduodenectomía , Vena Porta/cirugía , Procedimientos Quirúrgicos Vasculares , Anciano , Neoplasias de los Conductos Biliares/diagnóstico por imagen , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/patología , Colecistectomía/efectos adversos , Colecistectomía/mortalidad , Bases de Datos Factuales , Femenino , Hepatectomía/efectos adversos , Hepatectomía/mortalidad , Arteria Hepática/diagnóstico por imagen , Arteria Hepática/patología , Humanos , Tumor de Klatskin/diagnóstico por imagen , Tumor de Klatskin/mortalidad , Tumor de Klatskin/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pancreaticoduodenectomía/efectos adversos , Pancreaticoduodenectomía/mortalidad , Vena Porta/diagnóstico por imagen , Vena Porta/patología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , Procedimientos Quirúrgicos Vasculares/efectos adversos , Procedimientos Quirúrgicos Vasculares/mortalidadRESUMEN
CONTEXT: Parathyroid carcinoma is exceedingly rare in children. We describe a case of parathyroid cancer in a young female who was originally classified as benign and managed surgically. Upon her diagnosis with malignancy, concurrent with metastatic lung involvement, she was referred for medical and surgical palliation to control her symptomatic hypercalcemia. We briefly review published childhood cases, consider the challenges in differentiating malignant from benign hyperparathyroidism in this age group, and discuss the association of CDC73 mutations with parathyroid carcinoma. CASE PRESENTATION: A 13-year-old African American girl with a history of parathyroid adenoma, diagnosed at 8 years of age with multiple recurrences, presented with hypercalcemia and elevated parathyroid hormone when her disease had been reclassified as malignant. Germline gene analysis revealed a heterozygous partial deletion of CDC73. The patient underwent palliative surgery for disease metastatic to her lungs. She continues with medical management of her hypercalcemia. CONCLUSIONS: A case of pediatric parathyroid carcinoma associated with haploinsufficiency of CDC73 is discussed. We review all published cases of pediatric parathyroid carcinoma and offer diagnostic considerations for a parathyroid mass in a child.
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Adenoma/patología , Carcinoma/patología , Neoplasias de las Paratiroides/patología , Adenoma/genética , Adolescente , Carcinoma/genética , Femenino , Humanos , Recurrencia Local de Neoplasia/patología , Neoplasias de las Paratiroides/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
We investigated the use of robotic objective performance metrics (OPM) to predict number of cases to proficiency and independence among abdominal transplant fellows performing robot-assisted donor nephrectomy (RDN). 101 RDNs were performed by 5 transplant fellows from September 2020 to October 2023. OPM included fellow percent active control time (%ACT) and handoff counts (HC). Proficiency was defined as ACT ≥ 80% and HC ≤ 2, and independence as ACT ≥ 99% and HC ≤ 1. Case number was significantly associated with increasing fellow %ACT, with proficiency estimated at 14 cases and independence at 32 cases (R2 = 0.56, p < 0.001). Similarly, case number was significantly associated with decreasing HC, with proficiency at 18 cases and independence at 33 cases (R2 = 0.29, p < 0.001). Case number was not associated with total active console time (p = 0.91). Patient demographics, operative characteristics, and outcomes were not associated with OPM, except for donor estimated blood loss (EBL), which positively correlated with HC. Abdominal transplant fellows demonstrated proficiency at 14-18 cases and independence at 32-33 cases. Total active console time remained unchanged, suggesting that increasing fellow autonomy does not impede operative efficiency. These findings may serve as a benchmark for training abdominal transplant surgery fellows independently and safely in RDN.
Asunto(s)
Competencia Clínica , Donadores Vivos , Nefrectomía , Procedimientos Quirúrgicos Robotizados , Nefrectomía/métodos , Nefrectomía/educación , Humanos , Procedimientos Quirúrgicos Robotizados/educación , Procedimientos Quirúrgicos Robotizados/métodos , Femenino , Masculino , Trasplante de Riñón/métodos , Trasplante de Riñón/educación , Persona de Mediana Edad , Adulto , Benchmarking , BecasRESUMEN
BACKGROUND: An increasing number of transplant centers have adopted robot-assisted living donor nephrectomy. Thus, a transplant fellow assessment tool is needed for promoting operative independence in an objective and safe manner. METHODS: In this pilot study, data was prospectively collected on both fellow performance with focus on technique, efficiency, and communication ("overall RO-SCORE"), and operative steps ("operative steps RO-SCORE"). Robotic user performance metrics were analyzed from the da Vinci Xi system, including fellow percent active control time (ACT) and handoff counts. RESULTS: From July 2020 to February 2021, twenty-one robot-assisted donor nephrectomies were performed. In regression analysis, fellow performance (based on both RO-SCOREs and robot % ACT) was significantly associated with both time and case number, with time-to-independence modelled at 8.4-14.2 months, and case number-to-independence estimated at 15-22 cases. Robot user metrics provided valid objective measures alongside RO-SCOREs. CONCLUSIONS: This pilot study provides an effective assessment tool for promoting operative competency in robot-assisted donor nephrectomy among transplant fellows.
Asunto(s)
Laparoscopía , Procedimientos Quirúrgicos Robotizados , Robótica , Humanos , Nefrectomía/métodos , Donadores Vivos , Procedimientos Quirúrgicos Robotizados/métodos , Becas , Proyectos Piloto , Laparoscopía/métodosRESUMEN
Based on the concept that anticocaine antibodies could prevent inhaled cocaine from reaching its target receptors in the brain, an effective anticocaine vaccine could help reverse cocaine addiction. Leveraging the knowledge that E1(-)E3(-) adenovirus (Ad) gene transfer vectors are potent immunogens, we have developed a novel vaccine platform for addictive drugs by covalently linking a cocaine analog to the capsid proteins of noninfectious, disrupted Ad vector. The Ad-based anticocaine vaccine evokes high-titer anticocaine antibodies in mice sufficient to completely reverse, on a persistent basis, the hyperlocomotor activity induced by intravenous administration of cocaine.
Asunto(s)
Cocaína/análogos & derivados , Cocaína/inmunología , Trastornos Relacionados con Sustancias , Vacunas , Adenoviridae/genética , Animales , Anticuerpos/sangre , Cocaína/metabolismo , Virus Defectuosos/genética , Virus Defectuosos/inmunología , Virus Defectuosos/metabolismo , Femenino , Técnicas de Transferencia de Gen , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Locomoción/efectos de los fármacos , Locomoción/inmunología , Ratones , Ratones Endogámicos BALB C , Actividad Motora/efectos de los fármacos , Actividad Motora/inmunología , Trastornos Relacionados con Sustancias/inmunología , Trastornos Relacionados con Sustancias/prevención & control , Vacunas/administración & dosificación , Vacunas/inmunologíaRESUMEN
BACKGROUND: The objective of this study was to determine if there is an impact of surgical delay on 5-year overall survival (OS) from early stage colon cancer, and if so, to define how long surgery can safely be postponed. METHODS: Using the NCDB, we compared early (14-30 days) and delayed surgery (31-90 days) in patients with Stage I/II colon cancer. Outcomes included OS at five years and odds of death. RESULTS: Delayed resection conferred a decreased 5-year OS of 73.0% (95% CI, 72.6-73.4), compared to early resection 78.3% (95% CI, 77.9-78.8). When time to surgery was divided into one-week intervals, there was no difference in the odds of death with delay up to 35-41 days (6 weeks), but odds of death increased by 9% per week thereafter. CONCLUSIONS: These data support that definitive resection for early stage colon cancer may be safely delayed up to 6 weeks.
Asunto(s)
Adenocarcinoma/cirugía , Colectomía , Neoplasias del Colon/cirugía , Tiempo de Tratamiento , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Oportunidad Relativa , Sistema de Registros , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Estados UnidosRESUMEN
Although significant progress has been made in improving breast cancer survival, disparities among racial, ethnic, and underserved groups still exist. The goal of this investigation is to quantify racial disparities in the context of breast cancer care, examining the outcomes of recurrence and mortality in the city of Memphis. Patients with a biopsy-proven diagnosis of breast cancer from January 1, 2002, through December 31, 2012, were obtained from the tumor registry. Black patients were more likely to have advanced (II, III, or IV) clinical stage of breast cancer at diagnosis versus white patients. Black breast cancer patients had a two times higher odds of recurrence (95% confidence interval: 1.4, 3.0) after adjusting for race and clinical stage. Black breast cancer patients were 1.5 times more likely to die (95% confidence interval: 1.2, 1.8), after adjusting for race; age at diagnosis; clinical stage; ER, PR, HER2 status; and recurrence. Black women with stages 0, I, II, and III breast cancer all had a statistically significant longer median time from diagnosis to surgery than white women. Black patients were more likely to have advanced clinical stages of breast cancer at diagnosis versus white patients on a citywide level in Memphis. Black breast cancer patients have higher odds of recurrence and mortality when compared with white breast cancer patients, after adjusting for appropriate demographic and clinical attributes. More work is needed to develop, evaluate, and disseminate interventions to decrease inequities in timeliness of care for breast cancer patients.
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Negro o Afroamericano , Neoplasias de la Mama/etnología , Disparidades en el Estado de Salud , Disparidades en Atención de Salud/etnología , Población Blanca , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Mama in situ/diagnóstico , Carcinoma de Mama in situ/etnología , Carcinoma de Mama in situ/mortalidad , Carcinoma de Mama in situ/cirugía , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/etnología , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/cirugía , Carcinoma Intraductal no Infiltrante/diagnóstico , Carcinoma Intraductal no Infiltrante/etnología , Carcinoma Intraductal no Infiltrante/mortalidad , Carcinoma Intraductal no Infiltrante/cirugía , Carcinoma Lobular/diagnóstico , Carcinoma Lobular/etnología , Carcinoma Lobular/mortalidad , Carcinoma Lobular/cirugía , Femenino , Estudios de Seguimiento , Accesibilidad a los Servicios de Salud , Humanos , Modelos Logísticos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/etnología , Recurrencia Local de Neoplasia/mortalidad , Sistema de Registros , Estudios Retrospectivos , Tennessee , Adulto JovenRESUMEN
The receptor Flt3 and its ligand Flt3L are both critical for dendritic cell (DC) development, but DC deficiency is more severe in Flt3l-/- mice than in Flt3-/- mice. This has led to speculation that Flt3L binds to another receptor that also supports DC development. However, we found that Flt3L administration does not generate DCs in Flt3-/- mice, arguing against a second receptor. Instead, Flt3-/- DC progenitors matured in response to macrophage colony-stimulating factor (M-CSF) or stem cell factor, and deletion of Csf1r in Flt3-/- mice further reduced DC development, indicating that these cytokines could compensate for Flt3. Surprisingly, Flt3-/- DC progenitors displayed enhanced M-CSF signaling, suggesting that loss of Flt3 increased responsiveness to other cytokines. In agreement, deletion of Flt3 in Flt3l-/- mice paradoxically rescued their severe DC deficiency. Thus, multiple cytokines can support DC development, and the discrepancy between Flt3-/- and Flt3l-/- mice results from the increased sensitivity of Flt3-/- progenitors to these cytokines.
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Citocinas/metabolismo , Proteínas de la Membrana/deficiencia , Transducción de Señal , Tirosina Quinasa 3 Similar a fms/deficiencia , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Eliminación de Gen , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Células Madre/farmacología , Células Madre/citología , Células Madre/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
During the process of cross-presentation, viral or tumor-derived antigens are presented to CD8+ T cells by Batf3-dependent CD8α+/XCR1+ classical dendritic cells (cDC1s). We designed a functional CRISPR screen for previously unknown regulators of cross-presentation, and identified the BEACH domain-containing protein WDFY4 as essential for cross-presentation of cell-associated antigens by cDC1s in mice. However, WDFY4 was not required for major histocompatibility complex class II presentation, nor for cross-presentation by monocyte-derived dendritic cells. In contrast to Batf3 -/- mice, Wdfy4 -/- mice displayed normal lymphoid and nonlymphoid cDC1 populations that produce interleukin-12 and protect against Toxoplasma gondii infection. However, similar to Batf3 -/- mice, Wdfy4 -/- mice failed to prime virus-specific CD8+ T cells in vivo or induce tumor rejection, revealing a critical role for cross-presentation in antiviral and antitumor immunity.