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1.
Nat Commun ; 15(1): 6677, 2024 Aug 06.
Article de Anglais | MEDLINE | ID: mdl-39107283

RÉSUMÉ

Clarification of the cytotoxic function of T cells is crucial for understanding human immune responses and immunotherapy procedures. Here, we report a high-throughput Bessel oblique plane microscopy (HBOPM) platform capable of 3D live imaging and phenotyping of chimeric antigen receptor (CAR)-modified T-cell cytotoxicity against cancer cells. The HBOPM platform has the following characteristics: an isotropic subcellular resolution of 320 nm, large-scale scouting over 400 interacting cell pairs, long-term observation across 5 hours, and quantitative analysis of the Terabyte-scale 3D, multichannel, time-lapse image datasets. Using this advanced microscopy platform, several key subcellular events in CAR-T cells are captured and comprehensively analyzed; these events include the instantaneous formation of immune synapses and the sustained changes in the microtubing morphology. Furthermore, we identify the actin retrograde flow speed, the actin depletion coefficient, the microtubule polarization and the contact area of the CAR-T/target cell conjugates as essential parameters strongly correlated with CAR-T-cell cytotoxic function. Our approach will be useful for establishing criteria for quantifying T-cell function in individual patients for all T-cell-based immunotherapies.


Sujet(s)
Imagerie tridimensionnelle , Immunothérapie adoptive , Microtubules , Récepteurs chimériques pour l'antigène , Lymphocytes T , Humains , Récepteurs chimériques pour l'antigène/métabolisme , Récepteurs chimériques pour l'antigène/immunologie , Imagerie tridimensionnelle/méthodes , Immunothérapie adoptive/méthodes , Lymphocytes T/immunologie , Lymphocytes T/métabolisme , Microtubules/métabolisme , Lignée cellulaire tumorale , Synapses immunologiques/immunologie , Synapses immunologiques/métabolisme , Cytotoxicité immunologique , Actines/métabolisme , Microscopie/méthodes , Phénotype
2.
Stem Cell Res Ther ; 15(1): 257, 2024 Aug 13.
Article de Anglais | MEDLINE | ID: mdl-39135206

RÉSUMÉ

BACKGROUND: Using natural killer (NK) cells to treat hematopoietic and solid tumors has great promise. Despite their availability from peripheral blood and cord blood, stem cell-derived NK cells provide an "off-the-shelf" solution. METHODS: In this study, we developed two CAR-NK cells targeting PD-L1 derived from lentiviral transduction of human umbilical cord blood (UCB)-CD34+ cells and UCB-CD34+-derived NK cells. The transduction efficiencies and in vitro cytotoxic functions including degranulation, cytokine production, and cancer cell necrosis of both resultants PD-L1 CAR-NK cells were tested in vitro on two different PD-L1 low and high-expressing solid tumor cell lines. RESULTS: Differentiated CAR­modified UCB-CD34+ cells exhibited enhanced transduction efficiency. The expression of anti-PD-L1 CAR significantly (P < 0.05) enhanced the cytotoxicity of differentiated CAR­modified UCB-CD34+ cells and CAR-modified UCB-CD34+-derived NK cells against PD-L1 high-expressing tumor cell line. In addition, CAR-modified UCB-CD34+-derived NK cells significantly (P < 0.05) restored the tumor-killing ability of exhausted PD-1 high T cells. CONCLUSION: Considering the more efficient transduction in stem cells and the possibility of producing CAR-NK cell products with higher yields, this approach is recommended for studies in the field of CAR-NK cells. Also, a pre-clinical study is now necessary to evaluate the safety and efficacy of these two CAR-NK cells individually and in combination with other therapeutic approaches.


Sujet(s)
Antigènes CD34 , Antigène CD274 , Sang foetal , Cellules tueuses naturelles , Humains , Cellules tueuses naturelles/immunologie , Cellules tueuses naturelles/métabolisme , Antigène CD274/métabolisme , Antigène CD274/génétique , Antigène CD274/immunologie , Sang foetal/cytologie , Antigènes CD34/métabolisme , Lymphocytes T/immunologie , Lymphocytes T/métabolisme , Différenciation cellulaire , Récepteurs chimériques pour l'antigène/métabolisme , Récepteurs chimériques pour l'antigène/immunologie , Récepteur-1 de mort cellulaire programmée/métabolisme , Lignée cellulaire tumorale , Immunothérapie adoptive/méthodes , Tumeurs/thérapie , Tumeurs/immunologie , Tumeurs/anatomopathologie
3.
Virology ; 598: 110194, 2024 Oct.
Article de Anglais | MEDLINE | ID: mdl-39096774

RÉSUMÉ

RSV infection remains a serious threat to the children all over the world, especially, in the low-middle income countries. Vaccine delivery via the mucosa holds great potential for inducing local immune responses in the respiratory tract. Previously, we reported the development of highly immunogenic RSV virus-like-particles (RSV-VLPs) based on the conformationally stable prefusogenic-F protein (preFg), glycoprotein and matrix protein. Here, to explore whether mucosal delivery of RSV-VLPs is an effective strategy to induce RSV-specific mucosal and systemic immunity, RSV-VLPs were administered via the nasal, sublingual and pulmonary routes to BALB/c mice. The results demonstrate that immunization with the VLPs via the mucosal routes induced minimal mucosal response and yet facilitated modest levels of serum IgG antibodies, enhanced T cell responses and the expression of the lung-homing marker CXCR3 on splenocytes. Immunization with VLPs via all three mucosal routes provided protection against RSV challenge with no signs of RSV induced pathology.


Sujet(s)
Anticorps antiviraux , Souris de lignée BALB C , Infections à virus respiratoire syncytial , Vaccins contre les virus respiratoires syncytiaux , Vaccins à pseudo-particules virales , Protéines de fusion virale , Protéines de la matrice virale , Animaux , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , Vaccins contre les virus respiratoires syncytiaux/immunologie , Vaccins contre les virus respiratoires syncytiaux/administration et posologie , Souris , Anticorps antiviraux/sang , Anticorps antiviraux/immunologie , Vaccins à pseudo-particules virales/immunologie , Vaccins à pseudo-particules virales/administration et posologie , Protéines de fusion virale/immunologie , Protéines de fusion virale/génétique , Protéines de fusion virale/administration et posologie , Femelle , Protéines de la matrice virale/immunologie , Protéines de la matrice virale/administration et posologie , Protéines de la matrice virale/génétique , Immunité muqueuse , Immunoglobuline G/sang , Immunoglobuline G/immunologie , Virus respiratoire syncytial humain/immunologie , Poumon/virologie , Poumon/immunologie , Glycoprotéines/immunologie , Glycoprotéines/administration et posologie , Administration par voie muqueuse , Virus respiratoires syncytiaux/immunologie , Lymphocytes T/immunologie
4.
Emerg Microbes Infect ; 13(1): 2387448, 2024 Dec.
Article de Anglais | MEDLINE | ID: mdl-39109538

RÉSUMÉ

Therapeutics for eradicating hepatitis B virus (HBV) infection are still limited and current nucleos(t)ide analogs (NAs) and interferon are effective in controlling viral replication and improving liver health, but they cannot completely eradicate the hepatitis B virus and only a very small number of patients are cured of it. The TCR-like antibodies recognizing viral peptides presented on human leukocyte antigens (HLA) provide possible tools for targeting and eliminating HBV-infected hepatocytes. Here, we generated three TCR-like antibodies targeting three different HLA-A2.1-presented peptides derived from HBV core and surface proteins. Bispecific antibodies (BsAbs) were developed by fuzing variable fragments of these TCR-like mAbs with an anti-CD3ϵ antibody. Our data demonstrate that the BsAbs could act as T cell engagers, effectively redirecting and activating T cells to target HBV-infected hepatocytes in vitro and in vivo. In HBV-persistent mice expressing human HLA-A2.1, two infusions of BsAbs induced marked and sustained suppression in serum HBsAg levels and also reduced the numbers of HBV-positive hepatocytes. These findings highlighted the therapeutic potential of TCR-like BsAbs as a new strategy to cure hepatitis B.


Sujet(s)
Anticorps bispécifiques , Modèles animaux de maladie humaine , Virus de l'hépatite B , Hépatite B , Hépatocytes , Animaux , Anticorps bispécifiques/immunologie , Anticorps bispécifiques/pharmacologie , Hépatocytes/virologie , Hépatocytes/immunologie , Souris , Humains , Virus de l'hépatite B/immunologie , Virus de l'hépatite B/génétique , Hépatite B/immunologie , Hépatite B/virologie , Antigène HLA-A2/immunologie , Antigènes de surface du virus de l'hépatite B/immunologie , Récepteurs aux antigènes des cellules T/immunologie , Lymphocytes T/immunologie
5.
Commun Biol ; 7(1): 983, 2024 Aug 13.
Article de Anglais | MEDLINE | ID: mdl-39138287

RÉSUMÉ

The mechanism of action of bispecific antibodies (bsAbs) directing T-cell immunity to solid tumors is incompletely understood. Here, we screened a series of CD3xHER2 bsAbs using extracellular matrix (ECM) embedded breast cancer tumoroid arrays exposed to healthy donor-derived T-cells. An initial phase of random T-cell movement throughout the ECM (day 1-2), was followed by a bsAb-dependent phase of active T-cell recruitment to tumoroids (day 2-4), and tumoroid killing (day 4-6). Low affinity HER2 or CD3 arms were compensated for by increasing bsAb concentrations. Instead, a bsAb binding a membrane proximal HER2 epitope supported tumor killing whereas a bsAb binding a membrane distal epitope did not, despite similar affinities and intra-tumoroid localization of the bsAbs, and efficacy in 2D co-cultures. Initial T-cell-tumor contact through effective bsAbs triggered a wave of subsequent T-cell recruitment. This critical surge of T-cell recruitment was explained by paracrine signaling and preceded a full-scale T-cell tumor attack.


Sujet(s)
Anticorps bispécifiques , Antigènes CD3 , Communication paracrine , Lymphocytes T , Anticorps bispécifiques/pharmacologie , Anticorps bispécifiques/immunologie , Humains , Antigènes CD3/immunologie , Antigènes CD3/métabolisme , Lymphocytes T/immunologie , Femelle , Tumeurs du sein/immunologie , Tumeurs du sein/anatomopathologie , Récepteur ErbB-2/immunologie , Récepteur ErbB-2/métabolisme , Lignée cellulaire tumorale
6.
BMC Pulm Med ; 24(1): 392, 2024 Aug 13.
Article de Anglais | MEDLINE | ID: mdl-39138424

RÉSUMÉ

BACKGROUND: The immunologic features of nontuberculous mycobacterial pulmonary disease (NTM-PD) are largely unclear. This study investigated the immunologic features of NTM-PD using digital spatial profiling techniques. METHODS: Lung tissues obtained from six patients with NTM-PD between January 1, 2006, and December 31, 2020, at Seoul National University Hospital were subjected to RNA sequencing. Cores from the peribronchial areas were stained with CD3, CD68, and DNASyto13, and gene expression at the whole-transcriptome level was quantified using PCR amplification and Illumina sequencing. Lung tissues from six patients with bronchiectasis collected during the same period were used as controls. The RNA sequencing results were validated using immunohistochemistry (IHC) in another cohort (30 patients with NTM-PD and 15 patients with bronchiectasis). RESULTS: NTM-PD exhibited distinct gene expression patterns in T cells and macrophages. Gene set enrichment analysis revealed that pathways related to antigen presentation and processing were upregulated in NTM-PD, particularly in macrophages. Macrophages were more prevalent and the expression of genes associated with the M1 phenotype (CD40 and CD80) was significantly elevated. Although macrophages were activated in the NTM-PD group T cell activity was unaltered. Notably, expression of the costimulatory molecule CD28 was decreased in NTM-PD. IHC analysis showed that T cells expressing Foxp3 or TIM-3, which facilitate the regulatory functions of T cells, were increased. CONCLUSIONS: NTM-PD exhibits distinct immunologic signatures characterized by the activation of macrophages without T cell activation.


Sujet(s)
Infections à mycobactéries non tuberculeuses , Humains , Mâle , Infections à mycobactéries non tuberculeuses/immunologie , Infections à mycobactéries non tuberculeuses/génétique , Femelle , Adulte d'âge moyen , Sujet âgé , Transcriptome , Macrophages/immunologie , Macrophages/métabolisme , Poumon/microbiologie , Poumon/immunologie , Poumon/anatomopathologie , Mycobactéries non tuberculeuses/génétique , Mycobactéries non tuberculeuses/immunologie , Maladies pulmonaires/génétique , Maladies pulmonaires/microbiologie , Maladies pulmonaires/immunologie , Lymphocytes T/immunologie , Analyse de profil d'expression de gènes , Adulte , Dilatation des bronches/immunologie , Dilatation des bronches/génétique , Dilatation des bronches/microbiologie
7.
J Vis Exp ; (209)2024 Jul 19.
Article de Anglais | MEDLINE | ID: mdl-39141526

RÉSUMÉ

The identification and characterization of antigen-specific T cells during health and disease remains a key to improving our understanding of immune pathophysiology. The technical challenges of tracking antigen-specific T cell populations within the endogenous T cell repertoire have been greatly advanced by the development of peptide:MHC tetramer reagents. These fluorescently labeled soluble multimers of MHC class I or class II molecules complexed to antigenic peptide epitopes bind directly to T cells with corresponding T cell receptor (TCR) specificity and can, therefore, identify antigen-specific T cell populations in their native state without a requirement for a functional response induced by ex vivo stimulation. For exceedingly rare populations, tetramer-bound T cells can be magnetically enriched to increase the sensitivity and reliability of detection. As the investigation of tissue-resident T cell immunity deepens, there is a pressing need to identify antigen-specific T cells that traffic to and reside in nonlymphoid tissues. In this protocol, we present a detailed set of instructions for the isolation and characterization of antigen-specific T cells present within mouse lungs. This involves the isolation of T cells from digested lung tissue followed by a general T cell magnetic enrichment step and tetramer staining for flow cytometry analysis and sorting. The steps highlighted in this protocol utilize common techniques and readily available reagents, making it accessible for nearly any researcher engaged in mouse T cell immunology, and are highly adaptable for a variety of downstream analyses of any low frequency antigen-specific T cell population residing within the lungs.


Sujet(s)
Poumon , Animaux , Souris , Poumon/immunologie , Poumon/cytologie , Peptides/immunologie , Peptides/composition chimique , Lymphocytes T/immunologie , Complexe majeur d'histocompatibilité/immunologie , Déterminants antigéniques des lymphocytes T/immunologie
10.
Front Immunol ; 15: 1445634, 2024.
Article de Anglais | MEDLINE | ID: mdl-39148730

RÉSUMÉ

Non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of fat within the cytoplasm of hepatocytes (exceeding 5% of liver weight) in individuals without significant alcohol consumption, has rapidly evolved into a pressing global health issue, affecting approximately 25% of the world population. This condition, closely associated with obesity, type 2 diabetes, and the metabolic syndrome, encompasses a spectrum of liver disorders ranging from simple steatosis without inflammation to non-alcoholic steatohepatitis (NASH) and cirrhotic liver disease. Recent research has illuminated the complex interplay between metabolic and immune responses in the pathogenesis of NASH, underscoring the critical role played by T and B lymphocytes. These immune cells not only contribute to necroinflammatory changes in hepatic lobules but may also drive the onset and progression of liver fibrosis. This narrative review aims to provide a comprehensive exploration of the effector mechanisms employed by T cells, B cells, and their respective subpopulations in the pathogenesis of NASH. Understanding the immunological complexity of NASH holds profound implications for the development of targeted immunotherapeutic strategies to combat this increasingly prevalent and burdensome metabolic liver disease.


Sujet(s)
Lymphocytes B , Stéatose hépatique non alcoolique , Lymphocytes T , Humains , Stéatose hépatique non alcoolique/immunologie , Stéatose hépatique non alcoolique/anatomopathologie , Stéatose hépatique non alcoolique/étiologie , Lymphocytes B/immunologie , Animaux , Lymphocytes T/immunologie , Foie/immunologie , Foie/anatomopathologie
11.
Theranostics ; 14(11): 4481-4498, 2024.
Article de Anglais | MEDLINE | ID: mdl-39113807

RÉSUMÉ

Rationale: Since oncogene expression products often exhibit upregulation or abnormally activated activity, developing a technique to regulate abnormal protein levels represent a viable approach for treating tumors and protein abnormality-related diseases. Methods: We first screened out eMIATAC components with high targeted degradation efficiency and explored the mechanism by which eMIATAC induced target protein degradation, and verified the degradation efficiency of the target protein by protein imprinting and flow cytometry. Next, we recombined eMIATAC with some controllable elements to verify the regulatable degradation performance of the target protein. Subsequently, we constructed eMIATAC that can express targeted degradation of AKT1 and verified its effect on GBM cell development in vitro and in vivo. Finally, we concatenated eMIATAC with CAR sequences to construct CAR-T cells with low BATF protein levels and verified the changes in their anti-tumor efficacy. Results: we developed a system based on the endosome-microautophagy-lysosome pathway for degrading endogenous proteins: endosome-MicroAutophagy TArgeting Chimera (eMIATAC), dependent on Vps4A instead of lysosomal-associated membrane protein 2A (LAMP2A) to bind to the chaperone Hsc70 and the protein of interest (POI). The complex was then transported to the lysosome by late endosomes, where degradation occurred similarly to microautophagy. The eMIATACs demonstrated accuracy, efficiency, reversibility, and controllability in degrading the target protein EGFP. Moreover, eMIATAC exhibited excellent performance in knocking down POI when targeting endogenous proteins in vivo and in vitro. Conclusions: The eMIATACs could not only directly knock down abnormal proteins for glioma treatment but also enhance the therapeutic effect of CAR-T cell therapy for tumors by knocking down T cell exhaustion-related proteins. The newly developed eMIATAC system holds promise as a novel tool for protein knockdown strategies. By enabling direct control over endogenous protein levels, eMIATAC has the potential to revolutionize treatment for cancer and genetic diseases.


Sujet(s)
Autophagie , Endosomes , Immunothérapie adoptive , Protéolyse , Humains , Animaux , Endosomes/métabolisme , Lignée cellulaire tumorale , Souris , Immunothérapie adoptive/méthodes , Récepteurs chimériques pour l'antigène/métabolisme , Glioblastome/thérapie , Glioblastome/métabolisme , Glioblastome/anatomopathologie , Protéine de membrane-2 associée au lysosome/métabolisme , Protéine de membrane-2 associée au lysosome/génétique , Tests d'activité antitumorale sur modèle de xénogreffe , Protéines du choc thermique HSC70/métabolisme , Lysosomes/métabolisme , Lymphocytes T/métabolisme
12.
Front Immunol ; 15: 1425443, 2024.
Article de Anglais | MEDLINE | ID: mdl-39104538

RÉSUMÉ

T cells, as a major lymphocyte population involved in the adaptive immune response, play an important immunomodulatory role in the early stages of autoimmune diseases. Autophagy is a cellular catabolism mediated by lysosomes. Autophagy maintains cell homeostasis by recycling degraded cytoplasmic components and damaged organelles. Autophagy has a protective effect on cells and plays an important role in regulating T cell development, activation, proliferation and differentiation. Autophagy mediates the participation of T cells in the acquired immune response and plays a key role in antigen processing as well as in the maintenance of T cell homeostasis. In autoimmune diseases, dysregulated autophagy of T cells largely influences the pathological changes. Therefore, it is of great significance to study how T cells play a role in the immune mechanism of autoimmune diseases through autophagy pathway to guide the clinical treatment of diseases.


Sujet(s)
Maladies auto-immunes , Autophagie , Lymphocytes T , Humains , Autophagie/immunologie , Maladies auto-immunes/immunologie , Animaux , Lymphocytes T/immunologie , Activation des lymphocytes/immunologie
13.
Immunohorizons ; 8(8): 538-549, 2024 Aug 01.
Article de Anglais | MEDLINE | ID: mdl-39109956

RÉSUMÉ

Perfluorohexane sulfonate (PFHxS) is a member of the per- and polyfluoroalkyls (PFAS) superfamily of molecules, characterized by their fluorinated carbon chains and use in a wide range of industrial applications. PFHxS and perfluorooctane sulfonate are able to accumulate in the environment and in humans with the approximated serum elimination half-life in the range of several years. More recently, some PFAS compounds have also been suggested as potential immunosuppressants. In this study, we analyze immune cell numbers in mice following 28-d repeated oral exposure to potassium PFHxS at 12, 120, 1,200, and 12,000 ng/kg/d, with resulting serum levels ranging up to ∼1,600 ng/ml, approximating ranges found in the general population and at higher levels in PFAS workers. The immunosuppressant cyclophosphamide was analyzed as a positive control. B cells, T cells, and granulocytes from the bone marrow, liver, spleen, lymph nodes, and thymus were evaluated. We found that at these exposures, there was no effect of PFHxS on major T or B cell populations, macrophages, dendritic cells, basophils, mast cells, eosinophils, neutrophils, or circulating Ab isotypes. By contrast, mice exposed to cyclophosphamide exhibited depletion of several granulocyte and T and B cell populations in the thymus, bone marrow, and spleen, as well as reductions in IgG1, IgG2b, IgG2c, IgG3, IgE, and IgM. These data indicate that exposures of up to 12,000 ng/kg of PFHxS for 28 d do not affect immune cell numbers in naive mice, which provides valuable information for assessing the risks and health influences of exposures to this compound.


Sujet(s)
Fluorocarbones , Animaux , Souris , Lymphocytes B/immunologie , Lymphocytes B/effets des médicaments et des substances chimiques , Acides sulfoniques , Lymphocytes T/immunologie , Lymphocytes T/effets des médicaments et des substances chimiques , Femelle , Rate/immunologie , Rate/effets des médicaments et des substances chimiques , Rate/cytologie , Thymus (glande)/effets des médicaments et des substances chimiques , Thymus (glande)/immunologie , Granulocytes/effets des médicaments et des substances chimiques , Granulocytes/immunologie , Mâle
14.
Clin Lab Med ; 44(3): 479-493, 2024 Sep.
Article de Anglais | MEDLINE | ID: mdl-39089753

RÉSUMÉ

There are approximately 500 congenital disorders that impair immune cell development and/or function. Patients with these disorders may present with a wide range of symptoms, including increased susceptibility to infection, autoimmunity, autoinflammation, lymphoproliferation, and/or atopy. Flow cytometry-based immune phenotyping of T and B lymphocytes plays an essential role in the evaluation of patients with these presentations. In this review, we describe the clinical utility of flow cytometry as part of a comprehensive evaluation of immune function and how this testing may be used as a diagnostic tool to identify underlying aberrant immune pathways, monitor disease activity, and assess infection risk.


Sujet(s)
Lymphocytes B , Cytométrie en flux , Immunophénotypage , Lymphocytes T , Humains , Lymphocytes B/immunologie , Lymphocytes T/immunologie , Déficits immunitaires/diagnostic , Déficits immunitaires/immunologie
15.
Proc Natl Acad Sci U S A ; 121(32): e2400153121, 2024 Aug 06.
Article de Anglais | MEDLINE | ID: mdl-39088391

RÉSUMÉ

Although many cytokine pathways are important for dendritic cell (DC) development, it is less clear what cytokine signals promote the function of mature dendritic cells. The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of proinflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), Stat4-/- mice are resistant to the development of inflammation and paralysis. To define whether STAT4 is required for intrinsic signaling in mature DC function, we used conditional mutant mice in the EAE model. Deficiency of STAT4 in CD11c-expressing cells resulted in decreased T cell priming and inflammation in the central nervous system. EAE susceptibility was recovered following adoptive transfer of wild-type bone marrow-derived DCs to mice with STAT4-deficient DCs, but not adoptive transfer of STAT4- or IL-23R-deficient DCs. Single-cell RNA-sequencing (RNA-seq) identified STAT4-dependent genes in DC subsets that paralleled a signature in MS patient DCs. Together, these data define an IL-23-STAT4 pathway in DCs that is key to DC function during inflammatory disease.


Sujet(s)
Cellules dendritiques , Encéphalomyélite auto-immune expérimentale , Interleukine-23 , Facteur de transcription STAT-4 , Transduction du signal , Animaux , Facteur de transcription STAT-4/métabolisme , Cellules dendritiques/immunologie , Cellules dendritiques/métabolisme , Interleukine-23/métabolisme , Interleukine-23/immunologie , Souris , Encéphalomyélite auto-immune expérimentale/immunologie , Encéphalomyélite auto-immune expérimentale/métabolisme , Souris knockout , Sclérose en plaques/immunologie , Sclérose en plaques/métabolisme , Sclérose en plaques/anatomopathologie , Système nerveux central/métabolisme , Système nerveux central/immunologie , Inflammation/métabolisme , Inflammation/immunologie , Transfert adoptif , Souris de lignée C57BL , Humains , Lymphocytes T/immunologie , Lymphocytes T/métabolisme
16.
Oncol Rep ; 52(4)2024 Oct.
Article de Anglais | MEDLINE | ID: mdl-39129321

RÉSUMÉ

B­cell lymphoma is difficult to cure because of its biological and clinical heterogeneity, and due to native chemoresistance. Immunotherapies that overcome cancer­induced immune evasion have been the center of recent developments in oncology. This is emphasized by the accomplishment of various agents that disrupt programmed cell death protein 1 (PD­1)­mediated immune suppression in diverse tumors. However, while PD­1 blockade has been effective in numerous malignancies, a significant proportion of cancers, including B­cell lymphoma, show certain rates of primary resistance to these therapeutic strategies. Histone deacetylase inhibitors (HDACis) have exhibited anticancer activity though suppressing cell proliferation, inducing differentiation and triggering apoptosis. The present study aimed to explore a therapeutic strategy combining a HDACi (romidepsin) and PD­1 blockade (BMS­1) in B­cell lymphoma, utilizing a constructed mouse model of B­cell lymphoma. The IC50 of the two inhibitors was confirmed by MTT assay, and their inhibitory effects were revealed to be dose­ and time­dependent. The data demonstrated that the combined treatment of romidepsin and BMS­1 synergistically inhibited the growth of B­cell lymphoma. Furthermore, it was revealed that romidepsin and BMS­1 synergistically triggered apoptosis in mouse B­cell lymphoma. The synergistic effect of these agents was capable of activating tumor­infiltrating lymphocytes, particularly CD3+CD4+ and CD3+CD8+ T cells. The results of the present study underscore the potential of HDAC inhibition in conjunction with PD­1 blockade as a novel therapeutic approach for B­cell lymphoma, highlighting the synergistic effects of these two mechanisms in enhancing antitumor immunity.


Sujet(s)
Apoptose , Depsipeptides , Synergie des médicaments , Inhibiteurs de désacétylase d'histone , Lymphome B , Récepteur-1 de mort cellulaire programmée , Animaux , Inhibiteurs de désacétylase d'histone/pharmacologie , Inhibiteurs de désacétylase d'histone/usage thérapeutique , Souris , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Apoptose/effets des médicaments et des substances chimiques , Depsipeptides/pharmacologie , Depsipeptides/usage thérapeutique , Depsipeptides/administration et posologie , Lymphome B/traitement médicamenteux , Lymphome B/immunologie , Lymphome B/anatomopathologie , Humains , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Lymphocytes TIL/immunologie , Lymphocytes TIL/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Lymphocytes T/immunologie , Lymphocytes T/effets des médicaments et des substances chimiques , Évolution de la maladie , Tests d'activité antitumorale sur modèle de xénogreffe
17.
Emerg Microbes Infect ; 13(1): 2317909, 2024 Dec.
Article de Anglais | MEDLINE | ID: mdl-39133062

RÉSUMÉ

Tick-borne encephalitis virus (TBEV) infection may cause acute central nervous system inflammation varying in clinical manifestations and severity. A possible correlation of TBEV-specific antibody and cell-mediated immune responses, shortly after infection, with clinical manifestations, severity and long-term outcome has been poorly investigated. In a cohort of thirty early tick-borne encephalitis (TBE) patients, we assessed the magnitude, specificity and functional properties of TBEV-specific T-cell and antibody responses. These responses early during disease were assessed in view of clinical manifestations, severity and long-term outcome. TBEV-specific T-cell responses to C, E, NS1, and NS5 proteins were significantly lower in patients with severe acute illness than in patients with mild TBE. Lower T-cell responses to E, NS1, and NS5 proteins also correlated with the development of meningoencephalomyelitis. Virus-specific antibody titres early after infection did not correlate with disease severity, clinical manifestations, or long-term outcome in this study, possibly due to the small number of patients of which matching serum and peripheral blood mononuclear cells were available. The findings suggest that virus-specific T cells afford a certain degree of protection against the development of severe TBEV-induced disease.


Sujet(s)
Anticorps antiviraux , Virus de l'encéphalite à tiques (sous-groupe) , Encéphalites à tiques , Lymphocytes T , Encéphalites à tiques/immunologie , Encéphalites à tiques/virologie , Virus de l'encéphalite à tiques (sous-groupe)/immunologie , Humains , Lymphocytes T/immunologie , Anticorps antiviraux/sang , Anticorps antiviraux/immunologie , Mâle , Femelle , Adulte d'âge moyen , Adulte , Indice de gravité de la maladie , Sujet âgé , Protéines virales non structurales/immunologie
18.
Genome Biol ; 25(1): 214, 2024 Aug 09.
Article de Anglais | MEDLINE | ID: mdl-39123248

RÉSUMÉ

Analysis of clonal dynamics in human tissues is enabled by somatic genetic variation. Here, we show that analysis of mitochondrial mutations in single cells is dramatically improved in females when using X chromosome inactivation to select informative clonal mutations. Applying this strategy to human peripheral mononuclear blood cells reveals clonal structures within T cells that otherwise are blurred by non-informative mutations, including the separation of gamma-delta T cells, suggesting this approach can be used to decipher clonal dynamics of cells in human tissues.


Sujet(s)
Mutation , Analyse sur cellule unique , Inactivation du chromosome X , Humains , Femelle , Agranulocytes/métabolisme , Chromosomes X humains/génétique , Clones cellulaires , Lymphocytes T/métabolisme , Mâle , ADN mitochondrial/génétique
19.
Front Immunol ; 15: 1429205, 2024.
Article de Anglais | MEDLINE | ID: mdl-39100662

RÉSUMÉ

Islet transplantation is a promising therapy for diabetes treatment. However, the molecular underpinnings governing the immune response, particularly T-cell dynamics in syngeneic and allogeneic transplant settings, remain poorly understood. Understanding these T cell dynamics is crucial for enhancing graft acceptance and managing diabetes treatment more effectively. This study aimed to elucidate the molecular mechanisms, gene expression differences, biological pathway alterations, and intercellular communication patterns among T-cell subpopulations after syngeneic and allogeneic islet transplantation. Using single-cell RNA sequencing, we analyzed cellular heterogeneity and gene expression profiles using the Seurat package for quality control and dimensionality reduction through t-SNE. Differentially expressed genes (DEGs) were analyzed among different T cell subtypes. GSEA was conducted utilizing the HALLMARK gene sets from MSigDB, while CellChat was used to infer and visualize cell-cell communication networks. Our findings revealed genetic variations within T-cell subpopulations between syngeneic and allogeneic islet transplants. We identified significant DEGs across these conditions, highlighting molecular discrepancies that may underpin rejection or other immune responses. GSEA indicated activation of the interferon-alpha response in memory T cells and suppression in CD4+ helper and γδ T cells, whereas TNFα signaling via NFκB was particularly active in regulatory T cells, γδ T cells, proliferating T cells, and activated CD8+ T cells. CellChat analysis revealed complex communication patterns within T-cell subsets, notably between proliferating T cells and activated CD8+ T cells. In conclusion, our study provides a comprehensive molecular landscape of T-cell diversity in islet transplantation. The insights into specific gene upregulation in xenotransplants suggest potential targets for improving graft tolerance. The differential pathway activation across T-cell subsets underscores their distinct roles in immune responses posttransplantation.


Sujet(s)
Transplantation d'ilots de Langerhans , Analyse sur cellule unique , Transplantation homologue , Animaux , Souris , Analyse sur cellule unique/méthodes , Souris de lignée C57BL , Analyse de séquence d'ARN , Transcriptome , Transplantation isogénique , Analyse de profil d'expression de gènes , Diabète expérimental/immunologie , Diabète expérimental/génétique , Rejet du greffon/immunologie , Rejet du greffon/génétique , Mâle , Sous-populations de lymphocytes T/immunologie , Sous-populations de lymphocytes T/métabolisme , Souris de lignée BALB C , Lymphocytes T/immunologie , Lymphocytes T/métabolisme , Survie du greffon/immunologie , Survie du greffon/génétique
20.
Rinsho Ketsueki ; 65(7): 644-651, 2024.
Article de Japonais | MEDLINE | ID: mdl-39098015

RÉSUMÉ

T cell malignancies pose several unique issues for CAR-T cell therapy that were not significant concerns with CAR-T cells for B-cell malignancies. A general problem to consider in the production of CAR-T cells is "on target-off tumor toxicity." This occurs when the antigen targeted by the CAR-T cells is also expressed on normal cells, not just tumor cells, which causes CAR-T cells to damage these normal cells. In CAR-T cell therapy for T cell tumors, antigens expressed on T cells (such as CD5, CD7, etc.) are the targets, which leads to a problem known as "fratricide," where CAR-T cells kill each other. Other issues include T cell aplasia and contamination of CAR-T cell products with tumor cells. However, several recent clinical trials have shown excellent outcomes for CAR-T cell therapy when genome editing technology is used to overcome these issues by knocking out target antigens or T cell receptors. This review article outlines these challenges and their solutions and discusses the results of recent clinical trials.


Sujet(s)
Lymphocytes T , Humains , Lymphocytes T/immunologie , Immunothérapie adoptive/méthodes , Récepteurs aux antigènes des cellules T/immunologie , Récepteurs chimériques pour l'antigène/immunologie , Tumeurs/thérapie , Tumeurs/immunologie
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