RESUMO
Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons.
Assuntos
Células Matadoras Naturais , Análise de Célula Única , Humanos , Análise de Célula Única/métodos , Células Matadoras Naturais/imunologia , Transcriptoma , Neoplasias/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Tonsila Palatina/imunologia , Tonsila Palatina/citologia , Perfilação da Expressão Gênica , Pulmão/imunologia , Citocinas/metabolismoRESUMO
The nuclear corepressors NCOR1 and NCOR2 interact with transcription factors involved in B cell development and potentially link these factors to alterations in chromatin structure and gene expression. Herein, we demonstrate that Ncor1/2 deletion limits B cell differentiation via impaired recombination, attenuates pre-BCR signaling and enhances STAT5-dependent transcription. Furthermore, NCOR1/2-deficient B cells exhibited derepression of EZH2-repressed gene modules, including the p53 pathway. These alterations resulted in aberrant Rag1 and Rag2 expression and accessibility. Whole-genome sequencing of Ncor1/2 DKO B cells identified increased number of structural variants with cryptic recombination signal sequences. Finally, deletion of Ncor1 alleles in mice facilitated leukemic transformation, whereas human leukemias with less NCOR1 correlated with worse survival. NCOR1/2 mutations in human leukemia correlated with increased RAG expression and number of structural variants. These studies illuminate how the corepressors NCOR1/2 regulate B cell differentiation and provide insights into how NCOR1/2 mutations may promote B cell transformation.
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Hematopoese , Transdução de Sinais , Camundongos , Humanos , Animais , Proteínas Correpressoras , Núcleo Celular , Genômica , Correpressor 2 de Receptor Nuclear/genética , Correpressor 1 de Receptor Nuclear/genéticaRESUMO
Cerebral malaria is a deadly complication of Plasmodium infection and involves blood brain barrier (BBB) disruption following infiltration of white blood cells. During experimental cerebral malaria (ECM), mice inoculated with Plasmodium berghei ANKA-infected red blood cells develop a fatal CM-like disease caused by CD8+ T cell-mediated pathology. We found that treatment with interleukin-15 complex (IL-15C) prevented ECM, whereas IL-2C treatment had no effect. IL-15C-expanded natural killer (NK) cells were necessary and sufficient for protection against ECM. IL-15C treatment also decreased CD8+ T cell activation in the brain and prevented BBB breakdown without influencing parasite load. IL-15C induced NK cells to express IL-10, which was required for IL-15C-mediated protection against ECM. Finally, we show that ALT-803, a modified human IL-15C, mediates similar induction of IL-10 in NK cells and protection against ECM. These data identify a regulatory role for cytokine-stimulated NK cells in the prevention of a pathogenic immune response.
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Interleucina-10/imunologia , Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Malária Cerebral/imunologia , Plasmodium berghei/imunologia , Proteínas/farmacologia , Animais , Barreira Hematoencefálica/patologia , Encéfalo/imunologia , Encéfalo/patologia , Linfócitos T CD8-Positivos/imunologia , Interleucina-10/biossíntese , Ativação Linfocitária/imunologia , Malária Cerebral/microbiologia , Malária Cerebral/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Recombinantes de FusãoRESUMO
Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.
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Doenças Genéticas Inatas , Glucagon , Hipertensão Portal , Transplante de Fígado , Feminino , Humanos , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/cirurgia , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/cirurgia , Glucagon/sangue , Glucagon/genética , Hipertensão Portal/sangue , Hipertensão Portal/etiologia , Hipertensão Portal/genética , Hipertensão Portal/cirurgia , Hipertrofia/genética , Cirrose Hepática , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/cirurgia , Pancreatopatias/genética , Pancreatopatias/patologia , Pancreatopatias/cirurgia , Células Secretoras de Glucagon/patologiaRESUMO
Our phase I graft-versus-host disease (GVHD) prevention trial of JAK2 inhibitor, pacritinib, (recommended phase II dose: 100mg po BID day 0 to +70) plus sirolimus and tacrolimus (PAC/SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits IL-6 receptor activity and pathogenic Th1/Th17 differentiation in preclinical models and the phase I trial. Herein we report on our completed phase II trial of PAC/SIR/TAC after 8/8-HLA matched alloHCT. This single-arm phase II trial (NCT02891603) was powered to determine if PAC/SIR/TAC suppressed %pSTAT3+ CD4+ T cells at day +21 (primary endpoint: %pSTAT3+ CD4+ T cells ≤ 35%) and estimated grade II-IV acute GVHD by day +100. The impact of PAC/SIR/TAC on T cell subsets, CD28 (pS6 and pH3ser10), and IL-2 receptor (pSTAT5) signal transduction was also evaluated. Eligible patients (n=28) received alloHCT for hematologic malignancies or myeloproliferative neoplasms. Reduced or myeloablative intensity conditioning was permitted. PAC/SIR/TAC met the primary endpoint, reducing %pSTAT3+ CD4+ T cells to 9.62% at day +21. Th1/Th17 cells were decreased at day +21, increasing the ratio of Tregs to Th1 and Th17 cells with PAC/SIR/TAC at RP2D PAC compared to dose level 1 PAC. The cumulative incidence of grade II-IV acute GVHD by day +100 with PAC/SIR/TAC was similar to historic SIR/TAC values (46 v 43%). While PAC/SIR/TAC suppressed pSTAT3 and Th1/Th17 cells, the regimen did not improve acute GVHD prevention.
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The development of methods to derive induced pluripotent stem cells (iPSCs) has propelled stem cell research, and has the potential to revolutionize many areas of medicine, including cancer immunotherapy. These cells can be propagated limitlessly and can differentiate into nearly any specialized cell type. The ability to perform precise multigene engineering at the iPSC stage, generate master cell lines after clonal selection, and faithfully promote differentiation along natural killer (NK) cells and T-cell lineages is now leading to new opportunities for the administration of off-the-shelf cytotoxic lymphocytes with direct antigen targeting to treat patients with relapsed/refractory cancer. In this review, we highlight the recent progress in iPSC editing and guided differentiation in the development of NK- and T-cell products for immunotherapy. We also discuss some of the potential barriers that remain in unleashing the full potential of iPSC-derived cytotoxic effector cells in the adoptive transfer setting, and how some of these limitations may be overcome through gene editing.
Assuntos
Células-Tronco Pluripotentes Induzidas , Neoplasias , Humanos , Linfócitos T , Células Matadoras Naturais , Imunoterapia , Neoplasias/terapia , Imunoterapia AdotivaRESUMO
CMV can elicit adaptive immune features in both mouse and human NK cells. Mouse Ly49H+ NK cells expand 100- to 1000-fold in response to mouse CMV infection and persist for months after exposure. Human NKG2C+ NK cells also expand after human CMV (HCMV) infection and persist for months. The clonal expansion of adaptive NK cells is likely an energy-intensive process, and the metabolic requirements that support adaptive NK cell expansion and persistence remain largely uncharacterized. We previously reported that NK cells from HCMV-seropositive donors had increased maximum capacity for both glycolysis and mitochondrial oxidative phosphorylation relative to NK cells from HCMV-seronegative donors. In this article, we report an extension of this work in which we analyzed the metabolomes of NK cells from HCMV-seropositive donors with NKG2C+ expansions and NK cells from HCMV seronegative donors without such expansions. NK cells from HCMV+ donors exhibited striking elevations in purine and pyrimidine deoxyribonucleotides, along with moderate increases in plasma membrane components. Mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that, as a part of mTOR complex 1 (mTORC1), bridges nutrient signaling to metabolic processes necessary for cell growth. Signaling through mTORC1 induces both nucleotide and lipid synthesis. We observed elevated mTORC1 signaling on activation in both NKG2C- and NKG2C+ NK cells from HCMV+ donors relative to those from HCMV- donors, demonstrating a correlation between higher mTORC1 activity and synthesis of key metabolites for cell growth and division.
Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Humanos , Animais , Camundongos , Células Matadoras Naturais , Serina-Treonina Quinases TOR/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Metaboloma , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismoRESUMO
CMV infection alters NK cell phenotype and function toward a more memory-like immune state. These cells, termed adaptive NK cells, typically express CD57 and NKG2C but lack expression of the FcRγ-chain (gene: FCER1G, FcRγ), PLZF, and SYK. Functionally, adaptive NK cells display enhanced Ab-dependent cellular cytotoxicity (ADCC) and cytokine production. However, the mechanism behind this enhanced function is unknown. To understand what drives enhanced ADCC and cytokine production in adaptive NK cells, we optimized a CRISPR/Cas9 system to ablate genes from primary human NK cells. We ablated genes that encode molecules in the ADCC pathway, such as FcRγ, CD3ζ, SYK, SHP-1, ZAP70, and the transcription factor PLZF, and tested subsequent ADCC and cytokine production. We found that ablating the FcRγ-chain caused a modest increase in TNF-α production. Ablation of PLZF did not enhance ADCC or cytokine production. Importantly, SYK kinase ablation significantly enhanced cytotoxicity, cytokine production, and target cell conjugation, whereas ZAP70 kinase ablation diminished function. Ablating the phosphatase SHP-1 enhanced cytotoxicity but reduced cytokine production. These results indicate that the enhanced cytotoxicity and cytokine production of CMV-induced adaptive NK cells is more likely due to the loss of SYK than the lack of FcRγ or PLZF. We found the lack of SYK expression could improve target cell conjugation through enhanced CD2 expression or limit SHP-1-mediated inhibition of CD16A signaling, leading to enhanced cytotoxicity and cytokine production.
Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Humanos , Quinase Syk/genética , Sistemas CRISPR-Cas , Células Matadoras Naturais , Citocinas , Citotoxicidade Celular Dependente de AnticorposRESUMO
Autologous bone marrow mononuclear cells (BMMNCs) infused after severe traumatic brain injury have shown promise for treating the injury. We evaluated their impact in children, particularly their hypothesized ability to preserve the blood-brain barrier and diminish neuroinflammation, leading to structural CNS preservation with improved outcomes. We performed a randomized, double-blind, placebo-sham-controlled Bayesian dose-escalation clinical trial at two children's hospitals in Houston, TX and Phoenix, AZ, USA (NCT01851083). Patients 5-17â years of age with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8) were randomized to BMMNC or placebo (3:2). Bone marrow harvest, cell isolation and infusion were completed by 48 h post-injury. A Bayesian continuous reassessment method was used with cohorts of size 3 in the BMMNC group to choose the safest between two doses. Primary end points were quantitative brain volumes using MRI and microstructural integrity of the corpus callosum (diffusivity and oedema measurements) at 6â months and 12â months. Long-term functional outcomes and ventilator days, intracranial pressure monitoring days, intensive care unit days and therapeutic intensity measures were compared between groups. Forty-seven patients were randomized, with 37 completing 1-year follow-up (23 BMMNC, 14 placebo). BMMNC treatment was associated with an almost 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring days and 3-day (14%) reduction in intensive care unit (ICU) days. White matter volume at 1â year in the BMMNC group was significantly preserved compared to placebo [decrease of 19 891 versus 40 491, respectively; mean difference of -20 600, 95% confidence interval (CI): -35 868 to -5332; P = 0.01], and the number of corpus callosum streamlines was reduced more in placebo than BMMNC, supporting evidence of preserved corpus callosum connectivity in the treated groups (-431 streamlines placebo versus -37 streamlines BMMNC; mean difference of -394, 95% CI: -803 to 15; P = 0.055), but this did not reach statistical significance due to high variability. We conclude that autologous BMMNC infusion in children within 48 h after severe traumatic brain injury is safe and feasible. Our data show that BMMNC infusion led to: (i) shorter intensive care duration and decreased ICU intensity; (ii) white matter structural preservation; and (iii) enhanced corpus callosum connectivity and improved microstructural metrics.
Assuntos
Transplante de Medula Óssea , Lesões Encefálicas Traumáticas , Transplante Autólogo , Humanos , Criança , Lesões Encefálicas Traumáticas/terapia , Masculino , Feminino , Adolescente , Método Duplo-Cego , Pré-Escolar , Transplante de Medula Óssea/métodos , Transplante Autólogo/métodos , Imageamento por Ressonância Magnética , Resultado do Tratamento , Leucócitos Mononucleares/transplante , Teorema de BayesRESUMO
The incorporation of histone H3 variants has been implicated in the epigenetic memory of cellular state. Using genome editing with zinc-finger nucleases to tag endogenous H3.3, we report genome-wide profiles of H3 variants in mammalian embryonic stem cells and neuronal precursor cells. Genome-wide patterns of H3.3 are dependent on amino acid sequence and change with cellular differentiation at developmentally regulated loci. The H3.3 chaperone Hira is required for H3.3 enrichment at active and repressed genes. Strikingly, Hira is not essential for localization of H3.3 at telomeres and many transcription factor binding sites. Immunoaffinity purification and mass spectrometry reveal that the proteins Atrx and Daxx associate with H3.3 in a Hira-independent manner. Atrx is required for Hira-independent localization of H3.3 at telomeres and for the repression of telomeric RNA. Our data demonstrate that multiple and distinct factors are responsible for H3.3 localization at specific genomic locations in mammalian cells.
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Histonas/análise , Telômero/química , Animais , Sítios de Ligação , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células-Tronco Embrionárias/metabolismo , Genoma , Chaperonas de Histonas/genética , Chaperonas de Histonas/metabolismo , Histonas/genética , Histonas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Telômero/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Sítio de Iniciação de TranscriçãoRESUMO
BACKGROUND: Natural killer (NK) cells are dysfunctional in chronic human immunodeficiency virus (HIV) infection as they are not able to clear virus. We hypothesized that an infusion of NK cells, supported by interleukin 2 (IL-2) or IL-15, could decrease virus-producing cells in the lymphatic tissues. METHODS: We conducted a phase 1 pilot study in 6 persons with HIV (PWH), where a single infusion of haploidentical related donor NK cells was given plus either IL-2 or N-803 (an IL-15 superagonist). RESULTS: The approach was well tolerated with no unexpected adverse events. We did not pretreat recipients with cyclophosphamide or fludarabine to "make immunologic space," reasoning that PWH on stable antiretroviral treatment remain T-cell depleted in lymphatic tissues. We found donor cells remained detectable in blood for up to 8 days (similar to what is seen in cancer pretreatment with lymphodepleting chemotherapy) and in the lymph nodes and rectum up to 28 days. There was a moderate decrease in the frequency of viral RNA-positive cells in lymph nodes. CONCLUSIONS: There was a moderate decrease in HIV-producing cells in lymph nodes. Further studies are warranted to determine the impact of healthy NK cells on HIV reservoirs and if restoring NK-cell function could be part of an HIV cure strategy. Clinical Trials Registration. NCT03346499 and NCT03899480.
Assuntos
Infecções por HIV , Interleucina-15 , Interleucina-2 , Células Matadoras Naturais , Humanos , Células Matadoras Naturais/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Infecções por HIV/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Adulto , Projetos Piloto , Feminino , Carga Viral , Linfonodos/imunologia , HIV-1/imunologiaRESUMO
We demonstrate that single-atom alloy catalysts can be made by exposing physical mixtures of monometallic supported Cu and Pd catalysts to vinyl acetate (VA) synthesis reaction conditions. This reaction induces the formation of mobile clusters of metal diacetate species that drive extensive metal nanoparticle restructuring, leading to atomic dispersion of the precious metal, smaller nanoparticle sizes than the parent catalysts, and high activity and selectivity for both VA synthesis and ethanol dehydrogenation reactions. This approach is scalable and appears to be generalizable to other alloy catalysts.
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Comparison of bonding and electronic structural features between trivalent lanthanide (Ln) and actinide (An) complexes across homologous series' of molecules can provide insights into subtle and overt periodic trends. Of keen interest and debate is the extent to which the valence f- and d-orbitals of trivalent Ln/An ions engage in covalent interactions with different ligand donor functionalities and, crucially, how bonding differences change as both the Ln and An series are traversed. Synthesis and characterization (SC-XRD, NMR, UV-vis-NIR, and computational modeling) of the homologous lanthanide and actinide N-heterocyclic carbene (NHC) complexes [M(C5Me5)2(X)(IMe4)] {X = I, M = La, Ce, Pr, Nd, U, Np, Pu; X = Cl, M = Nd; X = I/Cl, M = Nd, Am; and IMe4 = [C(NMeCMe)2]} reveals consistently shorter An-C vs Ln-C distances that do not substantially converge upon reaching Am3+/Nd3+ comparison. Specifically, the difference of 0.064(6) Å observed in the La/U pair is comparable to the 0.062(4) Å difference observed in the Nd/Am pair. Computational analyses suggest that the cause of this unusual observation is rooted in the presence of π-bonding with the valence d-orbital manifold in actinide complexes that is not present in the lanthanide congeners. This is in contrast to other documented cases of shorter An-ligand vs Ln-ligand distances, which are often attributed to increased 5f vs 4f radial diffusivity leading to differences in 4f and 5f orbital bonding involvement. Moreover, in these traditional observations, as the 5f series is traversed, the 5f manifold contracts such that by americium structural studies often find no statistically significant Am3+vs Nd3+ metal-ligand bond length differences.
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BACKGROUND: In the United States, over 80% of tuberculosis (TB) disease cases are estimated to result from reactivation of latent TB infection (LTBI) acquired more than 2 years previously ("reactivation TB"). We estimated reactivation TB rates for the US population with LTBI, overall, by age, sex, race-ethnicity, and US-born status, and for selected comorbidities (diabetes, end-stage renal disease, and HIV). METHODS: We collated nationally representative data for 2011-2012. Reactivation TB incidence was based on TB cases reported to the National TB Surveillance System that were attributed to LTBI reactivation. Person-years at risk of reactivation TB were calculated using interferon-gamma release assay (IGRA) positivity from the National Health and Nutrition Examination Survey, published values for interferon-gamma release assay sensitivity and specificity, and population estimates from the American Community Survey. RESULTS: For persons aged ≥6 years with LTBI, the overall reactivation rate was estimated as 0.072 (95% uncertainty interval: 0.047, 0.12) per 100 person-years. Estimated reactivation rates declined with age. Compared to the overall population, estimated reactivation rates were higher for persons with diabetes (adjusted rate ratio [aRR] = 1.6 [1.5, 1.7]), end-stage renal disease (aRR = 9.8 [5.4, 19]), and HIV (aRR = 12 [10, 13]). CONCLUSIONS: In our study, individuals with LTBI faced small, non-negligible risks of reactivation TB. Risks were elevated for individuals with medical comorbidities that weaken immune function.
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Diabetes Mellitus , Infecções por HIV , Falência Renal Crônica , Mycobacterium tuberculosis , Tuberculose , Humanos , Estados Unidos/epidemiologia , Inquéritos Nutricionais , Tuberculose/epidemiologia , Tuberculose/diagnóstico , Falência Renal Crônica/epidemiologia , Infecções por HIV/epidemiologiaRESUMO
Substantial numbers of B cell leukemia and lymphoma patients relapse due to antigen loss or heterogeneity after anti-CD19 chimeric antigen receptor (CAR) T cell therapy. To overcome antigen escape and address antigen heterogeneity, we engineered induced pluripotent stem cell-derived NK cells to express both an NK cell-optimized anti-CD19 CAR for direct targeting and a high affinity, non-cleavable CD16 to augment antibody-dependent cellular cytotoxicity. In addition, we introduced a membrane-bound IL-15/IL-15R fusion protein to promote in vivo persistence. These engineered cells, termed iDuo NK cells, displayed robust CAR-mediated cytotoxic activity that could be further enhanced with therapeutic antibodies targeting B cell malignancies. In multiple in vitro and xenogeneic adoptive transfer models, iDuo NK cells exhibited robust anti-lymphoma activity. Furthermore, iDuo NK cells effectively eliminated both CD19+ and CD19- lymphoma cells and displayed a unique propensity for targeting malignant cells over healthy cells that expressed CD19, features not achievable with anti-CAR19 T cells. iDuo NK cells combined with therapeutic antibodies represent a promising approach to prevent relapse due to antigen loss and tumor heterogeneity in patients with B cell malignancies.
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Leucemia , Neoplasias , Humanos , Deriva e Deslocamento Antigênicos , Leucemia/terapia , Células Matadoras NaturaisRESUMO
Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.
Assuntos
Antineoplásicos/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Interleucina-15/administração & dosagem , Células Matadoras Naturais/transplante , Leucemia Mieloide Aguda , Proteínas Recombinantes de Fusão/administração & dosagem , Células Alógenas/imunologia , Feminino , Humanos , Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/terapia , MasculinoRESUMO
The mechanisms underlying human natural killer (NK) cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins after human cytomegalovirus (HCMV) infection. The absence of B and myeloid cell-related signaling protein expression in these NK cell subsets correlated with promoter DNA hypermethylation. Genome-wide DNA methylation patterns were strikingly similar between HCMV-associated adaptive NK cells and cytotoxic effector T cells but differed from those of canonical NK cells. Functional interrogation demonstrated altered cytokine responsiveness in adaptive NK cells that was linked to reduced expression of the transcription factor PLZF. Furthermore, subsets of adaptive NK cells demonstrated significantly reduced functional responses to activated autologous T cells. The present results uncover a spectrum of epigenetically unique adaptive NK cell subsets that diversify in response to viral infection and have distinct functional capabilities compared to canonical NK cell subsets.
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Anticorpos/imunologia , Infecções por Citomegalovirus/genética , Epigênese Genética/imunologia , Células Matadoras Naturais/imunologia , Fatores de Transcrição Kruppel-Like/imunologia , Linfócitos T Citotóxicos/imunologia , Imunidade Adaptativa , Proliferação de Células , Citomegalovirus/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/patologia , Infecções por Citomegalovirus/virologia , Metilação de DNA , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Células Matadoras Naturais/classificação , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Fatores de Transcrição Kruppel-Like/deficiência , Fatores de Transcrição Kruppel-Like/genética , Análise em Microsséries , Subfamília C de Receptores Semelhantes a Lectina de Células NK/deficiência , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Regiões Promotoras Genéticas , Proteína com Dedos de Zinco da Leucemia Promielocítica , Proteínas Tirosina Quinases/deficiência , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/imunologia , Receptores de IgG/deficiência , Receptores de IgG/genética , Receptores de IgG/imunologia , Transdução de Sinais , Quinase Syk , Linfócitos T Citotóxicos/patologia , Linfócitos T Citotóxicos/virologia , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/imunologiaRESUMO
The development of new catalyst materials for energy-efficient chemical synthesis is critical as over 80% of industrial processes rely on catalysts, with many of the most energy-intensive processes specifically using heterogeneous catalysis. Catalytic performance is a complex interplay of phenomena involving temperature, pressure, gas composition, surface composition, and structure over multiple length and time scales. In response to this complexity, the integrated approach to heterogeneous dilute alloy catalysis reviewed here brings together materials synthesis, mechanistic surface chemistry, reaction kinetics, in situ and operando characterization, and theoretical calculations in a coordinated effort to develop design principles to predict and improve catalytic selectivity. Dilute alloy catalystsâin which isolated atoms or small ensembles of the minority metal on the host metal lead to enhanced reactivity while retaining selectivityâare particularly promising as selective catalysts. Several dilute alloy materials using Au, Ag, and Cu as the majority host element, including more recently introduced support-free nanoporous metals and oxide-supported nanoparticle "raspberry colloid templated (RCT)" materials, are reviewed for selective oxidation and hydrogenation reactions. Progress in understanding how such dilute alloy catalysts can be used to enhance selectivity of key synthetic reactions is reviewed, including quantitative scaling from model studies to catalytic conditions. The dynamic evolution of catalyst structure and composition studied in surface science and catalytic conditions and their relationship to catalytic function are also discussed, followed by advanced characterization and theoretical modeling that have been developed to determine the distribution of minority metal atoms at or near the surface. The integrated approach demonstrates the success of bridging the divide between fundamental knowledge and design of catalytic processes in complex catalytic systems, which can accelerate the development of new and efficient catalytic processes.
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Ligas , Óxidos , Catálise , Domínio Catalítico , Metais , Oxirredução , Óxidos/químicaRESUMO
While the majority of American Academy of Dermatology members have some broad awareness of human trafficking, most are not aware of it in their communities or of the skin signs that could prompt identification of those being exploited, and have requested educational resources to assist patients affected by trafficking. The American Academy of Dermatology Ad Hoc Task Force on Dermatologic Resources for the Intervention and Prevention of Human Trafficking has been working to develop relevant resources, including an online toolkit on the American Academy of Dermatology website: https://www.aad.org/member/clinical-quality/clinical-care/human-trafficking.
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Dermatologia , Tráfico de Pessoas , Humanos , Estados Unidos , Comitês Consultivos , Academias e InstitutosRESUMO
In nuclear forensic analyses, measurements of actinide elements in a sample can assist with identifying interdicted or unknown materials. While these radiochemical signatures have been extensively investigated in uranium materials, less is known about bulk neptunium samples. This paper describes the measurement of trace actinide concentrations and isotopic profiles in a 237Np oxide sample. Uranium, plutonium, americium, and curium concentrations and isotopic profiles in the sample were determined and deemed potentially useful for distinguishing different sources of 237Np. Several different potential radiochronometry systems were also investigated; discordant results indicate that the Np sample was never completely purified of other actinide elements, or that subsequent contamination of the sample occurred. Few prior studies of neptunium materials have been reported, and these data suggest that trace actinide constituents could provide unique signatures to identify material out of regulatory control.