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1.
Leukemia ; 38(6): 1246-1255, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38724673

RESUMO

T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human-engineered cytotoxic CD4+ T cells. Single-cell RNA-seq of primary AML samples and CD4+ T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4+ T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cells in vitro. Killing-sensitive AML potently activated T cells before being killed, and upregulated ICAM1, a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing by primary ex vivo-isolated CD8+ T cells in vitro, and engineered CD4+ T cells in vitro and in vivo. While AML heterogeneity implies that multiple factors may determine their sensitivity to T cell killing, these data show that ICAM1 acts as an immune trigger, allowing T cell killing, and could play a role in AML patient survival in vivo.


Assuntos
Molécula 1 de Adesão Intercelular , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Molécula 1 de Adesão Intercelular/metabolismo , Molécula 1 de Adesão Intercelular/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Camundongos , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Prognóstico , Citotoxicidade Imunológica
2.
Toxicol In Vitro ; 96: 105783, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38278458

RESUMO

Arsenic compounds are common environmental toxicants worldwide and particularly enriched in the Northeast and the Southwestern United States, the Alps, and Bangladesh. Exposure to arsenic is linked with various detrimental health outcomes, including cancer, cognitive decline, and kidney damage. Our group has previously shown that arsenic trioxide alters T cell cytokine production. In the current study, we demonstrate that exposure to arsenic compounds alters B cell function in an in vitro influenza model. Human peripheral blood mononuclear cells (PBMCs) were isolated from blood and cultured with arsenic trioxide (As3O2) and subsequently challenged with Influenza A virus. B cells showed decreased expression of CD267, surface IgG and CD80 when treated with As3O2. Taken together, the data suggest that As3O2 affects the activation and surface antibody expression of human peripheral B cells. Overall, this suggests that As3O2 exposure could cause impaired humoral immunity.


Assuntos
Arsenicais , Orthomyxoviridae , Humanos , Trióxido de Arsênio/toxicidade , Leucócitos Mononucleares , Linfócitos B
3.
bioRxiv ; 2023 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-37790561

RESUMO

T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human engineered cytotoxic CD4 + T cells. Single-cell RNA-seq of primary AML samples and CD4 + T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4 + T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cells in vitro . Killing-sensitive AML potently activated T cells before being killed, and upregulated ICAM1 , a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing to primary ex vivo -isolated CD8 + T cells in vitro , and engineered CD4 + T cells in vitro and in vivo . Thus, ICAM1 on AML acts as an immune trigger, allowing T cell killing, and could affect AML patient survival in vivo . SIGNIFICANCE: AML is a common leukemia with sub-optimal outcomes. We show that AML transcriptional programs correlate with susceptibility to T cell killing. Killing resistance-associated AML programs are enriched in patients with poor survival. Killing-sensitive, but not resistant AML activate T cells and upregulate ICAM1 that binds to LFA-1 on T cells, allowing immune synapse formation which is critical for AML elimination.

4.
Immunopharmacol Immunotoxicol ; 45(4): 426-432, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36606674

RESUMO

OBJECTIVE: To test the effect of two dietary antioxidants: butylated hydroxytoluene (BHT) and 3-hydroxytyrosol (3-HT) in experimental food allergy. METHODS: BALB/c mice maintained on control diet or diet with BHT or 3-HT were sensitized with ovalbumin (OVA) or saline through transdermal exposure. Plasma OVA-specific IgE (OVA-IgE) and IgG1 (OVA-IgG1) antibody levels were determined using ELISA. Sensitized mice were challenged by oral gavage with OVA. Rectal temperature (RT) was measured before and after challenge. Mast cell degranulation was quantified by measuring the plasma levels of mouse mucosal mast cell protease-1 (mMCP-1). Flow cytometry was carried out to evaluate the percentage Th2 cells from the spleen. RESULTS: Mice on either a 3-HT or BHT diet showed a significantly decreased IgE response to OVA sensitization and less severe anaphylaxis, as evidenced by a diminished drop in body temperature, attenuated clinical signs, a more rapid recovery and decreased mast cell degranulation (as determined by lower plasma mMCP-1 levels). CONCLUSION: The present study indicates two dietary antioxidants: BHT and 3-HT may be protective against experimental food allergy. These results suggest 3-HT and BHT could potentially be useful for prevention of food allergy.


Assuntos
Hidroxitolueno Butilado , Hipersensibilidade Alimentar , Camundongos , Animais , Hidroxitolueno Butilado/farmacologia , Hidroxitolueno Butilado/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Hipersensibilidade Alimentar/prevenção & controle , Hipersensibilidade Alimentar/tratamento farmacológico , Mastócitos , Imunoglobulina E , Imunoglobulina G , Ovalbumina/farmacologia , Camundongos Endogâmicos BALB C , Modelos Animais de Doenças
5.
Food Chem Toxicol ; 165: 113122, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35580760

RESUMO

Arsenic is a persistent environmental contaminant that humans are exposed to primarily through contaminated water supplies. Arsenic has been shown to have numerous immunomodulatory effects, including deleterious effects on T cell function. However, the effect of arsenic on human T cell function in the context of influenza infection remains poorly characterized. The goal of this study was to determine the effects of arsenic on T cell activation and effector function in a human-relevant ex vivo model with influenza challenge. Flow cytometric analysis of T cells following the treatment of primary human peripheral blood mononuclear cells with environmentally relevant concentrations of arsenic trioxide and subsequent challenge with influenza A virus showed reduced viability, alterations in activation, a reduction in the population of memory cells, and reduced effector function evidenced by decreased IFNγ and granzyme B production. Overall, these studies suggest that arsenic impairs the human T cell response to influenza which corroborates epidemiological findings and could have further implications for antiviral immunity and vaccine efficacy.


Assuntos
Arsênio , Vírus da Influenza A , Influenza Humana , Arsênio/toxicidade , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Humanos , Leucócitos Mononucleares
6.
Drug Metab Dispos ; 50(4): 500-507, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34930784

RESUMO

Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a stress-activated transcription factor that is highly responsive to oxidative stress and electrophilic stimuli. Upon activation, Nrf2 upregulates a battery of cytoprotective genes meant to prevent cell death or damage. In many models of inflammation, Nrf2 protects against the immune response and decreases injury, including in the context of asthma and allergy. However, in some models of asthma and allergy, Nrf2 either does not play a role or can even exacerbate inflammation. In general, the reasons behind these discrepancies are not clear and the mechanisms by which Nrf2 modulates immune response are largely uncharacterized. The aim of this review is to highlight current literature assessing the role of Nrf2 in allergy and asthma to understand Nrf2 as a potential therapeutic target. SIGNIFICANCE STATEMENT: Nuclear factor erythroid-derived 2-like 2 (Nrf2) is an important immune mediator that modulates numerous immune cell types in various inflammatory diseases, including allergy and asthma. There is considerable interest in Nrf2 as a drug target in inflammation, which is complicated by the complex nature of Nrf2 in the immune system. This review focuses on the role of Nrf2 in asthma and allergy, including in regulating immune cell function and in detoxifying xenobiotics that exacerbate these diseases.


Assuntos
Asma , Hipersensibilidade , Fator 2 Relacionado a NF-E2 , Humanos , Inflamação/metabolismo , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia
7.
Curr Biol ; 29(7): 1137-1148.e4, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30905605

RESUMO

The trafficking of components within cilia, called intraflagellar transport (IFT), is powered by kinesin-2 and dynein-2 motors. Loss of function in any subunit of the heterotrimeric KIF3A/KIF3B/KAP kinesin-2 motor prevents ciliogenesis in mammalian cells and has hindered an understanding of how kinesin-2 motors function in cilium assembly and IFT. We used a chemical-genetic approach to generate an inhibitable KIF3A/KIF3B/KAP kinesin-2 motor (i3A/i3B) that is capable of rescuing wild-type (WT) motor function for cilium assembly and Hedgehog signaling in Kif3a/Kif3b double-knockout cells. We demonstrate that KIF3A/KIF3B function is required not just for cilium assembly but also for cilium maintenance, as inhibition of i3A/i3B blocks IFT within 2 min and leads to a complete loss of primary cilia within 8 h. In contrast, inhibition of dynein-2 has no effect on cilium maintenance within the same time frame. The kinetics of cilia loss indicate that two processes contribute to ciliary disassembly in response to cessation of anterograde IFT: a slow shortening that is steady over time and a rapid deciliation that occurs with stochastic onset. We also demonstrate that the kinesin-2 family members KIF3A/KIF3C and KIF17 cannot rescue ciliogenesis in Kif3a/Kif3b double-knockout cells or delay the loss of assembled cilia upon i3A/i3B inhibition. These results demonstrate that KIF3A/KIF3B/KAP is the sole and essential motor for cilium assembly and maintenance in mammalian cells. These findings highlight differences in how kinesin-2 motors were adapted for cilium assembly and IFT function across species.


Assuntos
Cílios/metabolismo , Flagelos/metabolismo , Cinesinas/metabolismo , Sequência de Aminoácidos , Animais , Camundongos , Células NIH 3T3 , Transporte Proteico
8.
Food Chem Toxicol ; 121: 231-236, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30171972

RESUMO

Tert-butylhydroquinone (tBHQ) is a commonly used food preservative with known immunomodulatory activity; however, there is little information regarding its role on natural killer (NK) cell activation and function. tBHQ is a known activator of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which results in induction of cytoprotective genes. Activation of Nrf2 has been shown to modulate immune responses in a number of different models. In addition, studies in our laboratory have shown that tBHQ inhibits numerous early events following T cell activation. In the current study, we investigated whether activated NK cells are impacted by tBHQ, since many signaling cascades that control NK cell effector function also contribute to T cell function. Splenocytes were isolated from female, wild-type C57Bl/6J mice and treated with 1 µM or 5 µM tBHQ. NK cell function was assessed after activation with phorbol 12-myristate 13-acetate (PMA) and ionomycin for 24 h. Activation of NK cells in the presence of tBHQ decreased total NK cell percentage, production of intracellular interferon gamma (IFNÉ£), granzyme B, and perforin, and induction of the cell surface proteins CD25 and CD69, which are markers of NK cell activation. In addition to NK cell effector function, NK cell maturation was also altered in response to tBHQ. Notably, this is the first study to demonstrate that the Nrf2 activator, tBHQ, negatively impacts effector function and maturation of NK cells.


Assuntos
Hidroquinonas/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Antioxidantes/farmacologia , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Granzimas/genética , Granzimas/metabolismo , Ionomicina/farmacologia , Células Matadoras Naturais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Perforina/genética , Perforina/metabolismo , Baço/citologia , Baço/efeitos dos fármacos
9.
Curr Biol ; 27(15): 2296-2306.e3, 2017 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-28736169

RESUMO

The motility and signaling functions of the primary cilium require a unique protein and lipid composition that is determined by gating mechanisms localized at the base of the cilium. Several protein complexes localize to the gating zone and may regulate ciliary protein composition; however, the mechanisms of ciliary gating and the dynamics of the gating components are largely unknown. Here, we used the BiFC (bimolecular fluorescence complementation) assay and report for the first time on the protein-protein interactions that occur between ciliary gating components and transiting cargoes during ciliary entry. We find that the nucleoporin Nup62 and the C termini of the nephronophthisis (NPHP) proteins NPHP4 and NPHP5 interact with the axoneme-associated kinesin-2 motor KIF17 and thus spatially map to the inner region of the ciliary gating zone. Nup62 and NPHP4 exhibit rapid turnover at the transition zone and thus define dynamic components of the gate. We find that B9D1, AHI1, and the N termini of NPHP4 and NPHP5 interact with the transmembrane protein SSTR3 and thus spatially map to the outer region of the ciliary gating zone. B9D1, AHI1, and NPHP5 exhibit little to no turnover at the transition zone and thus define components of a stable gating structure. These data provide the first comprehensive map of the molecular orientations of gating zone components along the inner-to-outer axis of the ciliary gating zone. These results advance our understanding of the functional roles of gating zone components in regulating ciliary protein composition.


Assuntos
Cílios/metabolismo , Cinesinas/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Animais , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/metabolismo , Cílios/genética , Cinesinas/metabolismo , Masculino , Camundongos , Células NIH 3T3 , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo
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