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1.
Nat Immunol ; 25(2): 294-306, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38238608

RESUMEN

Antigen-experienced CD8+ T cells form effector and central memory T cells (TEM and TCM cells, respectively); however, the mechanism(s) controlling their lineage plasticity remains incompletely understood. Here we show that the transcription cofactor Tle3 critically regulates TEM and TCM cell fates and lineage stability through dynamic redistribution in antigen-responding CD8+ T cell genome. Genetic ablation of Tle3 promoted CD8+ TCM cell formation at the expense of CD8+ TEM cells. Lineage tracing showed that Tle3-deficient CD8+ TEM cells underwent accelerated conversion into CD8+ TCM cells while retaining robust recall capacity. Tle3 acted as a coactivator for Tbet to increase chromatin opening at CD8+ TEM cell-characteristic sites and to activate CD8+ TEM cell signature gene transcription, while engaging Runx3 and Tcf1 to limit CD8+ TCM cell-characteristic molecular features. Thus, Tle3 integrated functions of multiple transcription factors to guard lineage fidelity of CD8+ TEM cells, and manipulation of Tle3 activity could favor CD8+ TCM cell production.


Asunto(s)
Linfocitos T CD8-positivos , Células T de Memoria , Factores de Transcripción/genética , Diferenciación Celular , Memoria Inmunológica/genética
2.
Nat Immunol ; 23(8): 1222-1235, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35882936

RESUMEN

CD8+ T cell homeostasis is maintained by the cytokines IL-7 and IL-15. Here we show that transcription factors Tcf1 and Lef1 were intrinsically required for homeostatic proliferation of CD8+ T cells. Multiomics analyses showed that Tcf1 recruited the genome organizer CTCF and that homeostatic cytokines induced Tcf1-dependent CTCF redistribution in the CD8+ T cell genome. Hi-C coupled with network analyses indicated that Tcf1 and CTCF acted cooperatively to promote chromatin interactions and form highly connected, dynamic interaction hubs in CD8+ T cells before and after cytokine stimulation. Ablating CTCF phenocopied the proliferative defects caused by Tcf1 and Lef1 deficiency. Tcf1 and CTCF controlled a similar set of genes that regulated cell cycle progression and promoted CD8+ T cell homeostatic proliferation in vivo. These findings identified CTCF as a Tcf1 cofactor and uncovered an intricate interplay between Tcf1 and CTCF that modulates the genomic architecture of CD8+ T cells to preserve homeostasis.


Asunto(s)
Linfocitos T CD8-positivos , Transducción de Señal , Linfocitos T CD8-positivos/metabolismo , Citocinas/metabolismo , Genómica , Homeostasis
3.
Nat Immunol ; 23(3): 386-398, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35190717

RESUMEN

The mechanisms underlying the heightened protection mediated by central memory CD8+ T (TCM) cells remain unclear. Here we show that the transcription factor Tcf1 was required in resting TCM cells to generate secondary effector CD8+ T cells and to clear pathogens during recall responses. Recall stimulation of CD8+ TCM cells caused extensive reprogramming of the transcriptome and chromatin accessibility, leading to rapid induction of glycolytic enzymes, cell cycle regulators and transcriptional regulators, including Id3. This cluster of genes did not require Tcf1 in resting CD8+ TCM cells, but depended on Tcf1 for optimal induction and chromatin opening in recall-stimulated CD8+ TCM cells. Tcf1 bound extensively to these recall-induced gene loci in resting CD8+ TCM cells and mediated chromatin interactions that positioned these genes in architectural proximity with poised enhancers. Thus, Tcf1 preprogramed a transcriptional program that supported the bioenergetic and proliferative needs of CD8+ TCM cells in case of a secondary challenge.


Asunto(s)
Linfocitos T CD8-positivos , Memoria Inmunológica , Animales , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/genética , Cromatina/metabolismo , Glucólisis/genética , Memoria Inmunológica/genética , Ratones , Ratones Endogámicos C57BL
4.
Nat Immunol ; 21(8): 938-949, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32572242

RESUMEN

The central nervous system (CNS) is classically viewed as immune-privileged; however, recent advances highlight interactions between the peripheral immune system and CNS in controlling infections and tissue homeostasis. Tissue-resident memory (TRM) CD8+ T cells in the CNS are generated after brain infections, but it is unknown whether CNS infection is required to generate brain TRM cells. We show that peripheral infections generate antigen-specific CD8+ memory T cells in the brain that adopt a unique TRM signature. Upon depletion of circulating and perivascular memory T cells, this brain signature was enriched and the surveilling properties of brain TRM cells was revealed by intravital imaging. Notably, peripherally induced brain TRM cells showed evidence of rapid activation and enhanced cytokine production and mediated protection after brain infections. These data reveal that peripheral immunizations can generate brain TRM cells and will guide potential use of T cells as therapeutic strategies against CNS infections and neurological diseases.


Asunto(s)
Encéfalo/inmunología , Linfocitos T CD8-positivos/inmunología , Infecciones del Sistema Nervioso Central/inmunología , Memoria Inmunológica/inmunología , Animales , Infecciones Bacterianas/inmunología , Encéfalo/citología , Activación de Linfocitos/inmunología , Ratones , Virosis/inmunología
7.
Nat Immunol ; 18(8): 931-939, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28604718

RESUMEN

Activated CD8+ T cells differentiate into cytotoxic effector (TEFF) cells that eliminate target cells. How TEFF cell identity is established and maintained is not fully understood. We found that Runx3 deficiency limited clonal expansion and impaired upregulation of cytotoxic molecules in TEFF cells. Runx3-deficient CD8+ TEFF cells aberrantly upregulated genes characteristic of follicular helper T (TFH) cell lineage, including Bcl6, Tcf7 and Cxcr5. Mechanistically, the Runx3-CBFß transcription factor complex deployed H3K27me3 to Bcl6 and Tcf7 genes to suppress the TFH program. Ablating Tcf7 in Runx3-deficient CD8+ TEFF cells prevented the upregulation of TFH genes and ameliorated their defective induction of cytotoxic genes. As such, Runx3-mediated Tcf7 repression coordinately enforced acquisition of cytotoxic functions and protected the cytotoxic lineage integrity by preventing TFH-lineage deviation.


Asunto(s)
Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Linfopoyesis/genética , Linfocitos T Citotóxicos/citología , Linfocitos T Colaboradores-Inductores/citología , Animales , Linaje de la Célula , Ensayo de Inmunoadsorción Enzimática , Epigénesis Genética , Regulación de la Expresión Génica , Factor Nuclear 1-alfa del Hepatocito/genética , Inmunohistoquímica , Ratones , Proteínas Proto-Oncogénicas c-bcl-6/genética , Receptores CXCR5/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ARN , Regulación hacia Arriba
8.
Nat Immunol ; 17(6): 695-703, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27111144

RESUMEN

The CD4(+) and CD8(+) T cell dichotomy is essential for effective cellular immunity. How individual T cell identity is established remains poorly understood. Here we show that the high-mobility group (HMG) transcription factors Tcf1 and Lef1 are essential for repressing CD4(+) lineage-associated genes including Cd4, Foxp3 and Rorc in CD8(+) T cells. Tcf1- and Lef1-deficient CD8(+) T cells exhibit histone hyperacetylation, which can be ascribed to intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1. Mutation of five conserved amino acids in the Tcf1 HDAC domain diminishes HDAC activity and the ability to suppress CD4(+) lineage genes in CD8(+) T cells. These findings reveal that sequence-specific transcription factors can utilize intrinsic HDAC activity to guard cell identity by repressing lineage-inappropriate genes.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Histona Desacetilasas/metabolismo , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Acetilación , Animales , Diferenciación Celular/genética , Linaje de la Célula/genética , Células Cultivadas , Femenino , Regulación de la Expresión Génica , Factor Nuclear 1-alfa del Hepatocito/genética , Histona Desacetilasas/genética , Factor de Unión 1 al Potenciador Linfoide/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación/genética , Dominios Proteicos/genética
9.
Nat Immunol ; 16(9): 980-90, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26214741

RESUMEN

Follicular helper T cells (T(FH) cells) are specialized effector CD4(+) T cells that help B cells develop germinal centers (GCs) and memory. However, the transcription factors that regulate the differentiation of T(FH) cells remain incompletely understood. Here we report that selective loss of Lef1 or Tcf7 (which encode the transcription factor LEF-1 or TCF-1, respectively) resulted in T(FH) cell defects, while deletion of both Lef1 and Tcf7 severely impaired the differentiation of T(FH) cells and the formation of GCs. Forced expression of LEF-1 enhanced T(FH) differentiation. LEF-1 and TCF-1 coordinated such differentiation by two general mechanisms. First, they established the responsiveness of naive CD4(+) T cells to T(FH) cell signals. Second, they promoted early T(FH) differentiation via the multipronged approach of sustaining expression of the cytokine receptors IL-6Rα and gp130, enhancing expression of the costimulatory receptor ICOS and promoting expression of the transcriptional repressor Bcl6.


Asunto(s)
Diferenciación Celular/inmunología , Receptor gp130 de Citocinas/inmunología , Proteínas de Unión al ADN/inmunología , Centro Germinal/inmunología , Factor Nuclear 1-alfa del Hepatocito/inmunología , Factor de Unión 1 al Potenciador Linfoide/inmunología , Receptores de Interleucina-6/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Linfocitos B/inmunología , Diferenciación Celular/genética , Receptor gp130 de Citocinas/genética , Proteínas de Unión al ADN/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Centro Germinal/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Factor de Unión 1 al Potenciador Linfoide/genética , Ratones , Proteínas Proto-Oncogénicas c-bcl-6 , Receptores de Interleucina-6/genética , Linfocitos T Colaboradores-Inductores/metabolismo
10.
Immunity ; 45(6): 1341-1354, 2016 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-27986453

RESUMEN

Differentiation of effector and memory CD8+ T cells is accompanied by extensive changes in the transcriptome and histone modifications at gene promoters; however, the enhancer repertoire and associated gene regulatory networks are poorly defined. Using histone mark chromatin immunoprecipitation coupled with deep sequencing, we mapped the enhancer and super-enhancer landscapes in antigen-specific naive, differentiated effector, and central memory CD8+ T cells during LCMV infection. Epigenomics-based annotation revealed a highly dynamic repertoire of enhancers, which were inherited, de novo activated, decommissioned and re-activated during CD8+ T cell responses. We employed a computational algorithm to pair enhancers with target gene promoters. On average, each enhancer targeted three promoters and each promoter was regulated by two enhancers. By identifying enriched transcription factor motifs in enhancers, we defined transcriptional regulatory circuitry at each CD8+ T cell response stage. These multi-dimensional datasets provide a blueprint for delineating molecular mechanisms underlying functional differentiation of CD8+ T cells.


Asunto(s)
Infecciones por Arenaviridae/inmunología , Linfocitos T CD8-positivos/inmunología , Elementos de Facilitación Genéticos/inmunología , Regulación de la Expresión Génica/inmunología , Activación de Linfocitos/inmunología , Algoritmos , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Inmunoprecipitación de Cromatina , Biología Computacional/métodos , Modelos Animales de Enfermedad , Elementos de Facilitación Genéticos/genética , Epigenómica/métodos , Redes Reguladoras de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Activación de Linfocitos/genética , Virus de la Coriomeningitis Linfocítica , Ratones , Regiones Promotoras Genéticas/genética , Regiones Promotoras Genéticas/inmunología
11.
Neurobiol Dis ; 199: 106582, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38942325

RESUMEN

Human beings are living longer than ever before and aging is accompanied by an increased incidence of motor deficits, including those associated with the neurodegenerative conditions, Parkinson's disease (PD) and Huntington's disease (HD). However, the biological correlates underlying this epidemiological finding, especially the functional basis at the synapse level, have been elusive. This study reveals that motor skill performance examined via rotarod, beam walking and pole tests is impaired in aged mice. This study, via electrophysiology recordings, further identifies an aging-related reduction in the efficacy of inhibitory synaptic transmission onto dorsolateral striatum (DLS) indirect-pathway medium spiny neurons (iMSNs), i.e., a disinhibition effect on DLS iMSNs. In addition, pharmacologically enhancing the activity of DLS iMSNs by infusing an adenosine A2A receptor (A2AR) agonist, which presumably mimics the disinhibition effect, impairs motor skill performance in young mice, simulating the behavior in aged naïve mice. Conversely, pharmacologically suppressing the activity of DLS iMSNs by infusing an A2AR antagonist, in order to offset the disinhibition effect, restores motor skill performance in aged mice, mimicking the behavior in young naïve mice. In conclusion, this study identifies a functional inhibitory synaptic plasticity in DLS iMSNs that likely contributes to the aging-related motor skill deficits, which would potentially serve as a striatal synaptic basis underlying age being a prominent risk factor for neurodegenerative motor deficits.


Asunto(s)
Envejecimiento , Cuerpo Estriado , Neuronas , Transmisión Sináptica , Animales , Envejecimiento/fisiología , Transmisión Sináptica/fisiología , Transmisión Sináptica/efectos de los fármacos , Neuronas/fisiología , Ratones , Masculino , Ratones Endogámicos C57BL , Globo Pálido , Trastornos de la Destreza Motora/fisiopatología , Destreza Motora/fisiología , Receptor de Adenosina A2A/metabolismo
12.
J Antimicrob Chemother ; 79(2): 417-428, 2024 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-38267384

RESUMEN

OBJECTIVES: The growing occurrence of bacterial resistance has spawned the development of novel antimicrobial agents. Antimicrobial peptides, a class of small molecules with antimicrobial activity, have been regarded as the ideal alternatives to antibiotics. METHODS: In this study, we amplified a new type of Zophobas atratus coleoptericin (denoted coleoptericin B) through rapid amplification of cDNA ends (RACE) PCR and expressed recombinant Z. atratus coleoptericin B (rZA-col B) by prokaryotic expression. Subsequently, we evaluated the antimicrobial effect and biocompatibility of rZA-col B in vivo, investigated its antimicrobial mechanism, and assessed its therapeutic effect in a murine model of mastitis caused by MDR Klebsiella pneumoniae. RESULTS: The in vivo studies demonstrated that rZA-col B possesses broad-spectrum antimicrobial activity against both Gram-positive and Gram-negative bacteria. It exhibited less than 1.5% haemolysis and 10% cytotoxicity, even at a concentration of 128 µM. Additionally, rZA-col B had a minimal risk of inducing drug resistance. Furthermore, rZA-col B could disrupt the integrity of bacterial membranes, induce membrane permeabilization and ultimately lead to bacterial death. Importantly, rZA-col B also alleviated mastitis caused by MDR K. pneumoniae in a murine model by enhancing bacterial clearance, reducing neutrophil infiltration, decreasing TNF-α and IL-1ß expression, and protecting the mammary barrier. CONCLUSIONS: rZA-col B may be a promising antibacterial agent to combat MDR bacterial infection.


Asunto(s)
Antiinfecciosos , Mastitis , Femenino , Ratones , Animales , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Klebsiella pneumoniae , Modelos Animales de Enfermedad , Bacterias Gramnegativas , Bacterias Grampositivas , Péptidos/farmacología , Antiinfecciosos/farmacología , Mastitis/tratamiento farmacológico , Pruebas de Sensibilidad Microbiana
13.
Cereb Cortex ; 33(5): 1595-1609, 2023 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-35524719

RESUMEN

Adverse experience, such as social isolation, during adolescence is one of the major causes of neuropsychiatric disorders that extend from adolescence into adulthood, such as substance addiction, obsessive-compulsive disorder, and eating disorders leading to obesity. A common behavioral feature of these neuropsychiatric disorders is a shift in the balance of decision-making strategy from goal-directed action to habitual response. This study has verified that adolescent social isolation directly shifts the balance of decision-making strategy from goal-directed action to habitual response, and that it cannot be reversed by simple regrouping. This study has further revealed that adolescent social isolation induces a suppression in the excitatory neurotransmission onto the direct-pathway medium spiny neurons of the dorsomedial striatum (DMS), and that chemogenetically compensating this suppression effect shifts the balance of decision-making strategy from habitual response back to goal-directed action. These findings suggest that the plasticity in the DMS causes the shift in the balance of decision-making strategy, which would potentially help to develop a general therapy to treat the various neuropsychiatric disorders caused by adolescent social isolation. Such a study is especially necessary under the circumstances that social distancing and lockdown have caused during times of world-wide, society-wide pandemic.


Asunto(s)
Cuerpo Estriado , Objetivos , Adolescente , Humanos , Cuerpo Estriado/fisiología , Motivación , Transmisión Sináptica/fisiología , Aislamiento Social
14.
Int J Mol Sci ; 25(12)2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38928408

RESUMEN

Trueperella pyogenes is an important opportunistic pathogenic bacterium widely distributed in the environment. Pyolysin (PLO) is a primary virulence factor of T. pyogenes and capable of lysing many different cells. PLO is a member of the cholesterol-dependent cytolysin (CDC) family of which the primary structure only presents a low level of homology with other members from 31% to 45%. By deeply studying PLO, we can understand the overall pathogenic mechanism of CDC family proteins. This study established a mouse muscle tissue model infected with recombinant PLO (rPLO) and its single-point mutations, rPLO N139K and rPLO F240A, and explored its mechanism of causing inflammatory damage. The inflammatory injury abilities of rPLO N139K and rPLO F240A are significantly reduced compared to rPLO. This study elaborated on the inflammatory mechanism of PLO by examining its unit point mutations in detail. Our data also provide a theoretical basis and practical significance for future research on toxins and bacteria.


Asunto(s)
Proteínas Bacterianas , Proteínas Hemolisinas , Proteína con Dominio Pirina 3 de la Familia NLR , Mutación Puntual , Animales , Ratones , Proteínas Hemolisinas/metabolismo , Proteínas Hemolisinas/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Inflamación/metabolismo , Inflamación/genética , Potasio/metabolismo , Transducción de Señal , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/genética , Inflamasomas/metabolismo , Humanos
15.
Int J Mol Sci ; 25(7)2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38612785

RESUMEN

Trueperella pyogenes can cause various infections in the organs and tissues of different livestock (including pigs, cows, goats, and sheep), including mastitis, endometritis, pneumonia, or abscesses. Moreover, diseases induced by T. pyogenes cause significant economic losses in animal husbandry. In recent large-scale investigations, T. pyogenes has been identified as one of the main pathogens causing endometritis in lactating cows. However, the main treatment for the above-mentioned diseases is still currently antibiotic therapy. Understanding the impact of endometritis associated with T. pyogenes on the fertility of cows can help optimize antibiotic treatment for uterine diseases, thereby strategically concentrating the use of antimicrobials on the most severe cases. Therefore, it is particularly important to continuously monitor the prevalence of T. pyogenes and test its drug resistance. This study compared the uterine microbiota of healthy cows and endometritis cows in different cattle farms, investigated the prevalence of T. pyogenes, evaluated the genetic characteristics and population structure of isolated strains, and determined the virulence genes and drug resistance characteristics of T. pyogenes. An amount of 186 dairy cows were involved in this study and 23 T. pyogenes strains were isolated and identified from the uterine lavage fluid of dairy cows with or without endometritis.


Asunto(s)
Endometritis , Femenino , Humanos , Bovinos , Animales , Ovinos , Porcinos , Endometritis/veterinaria , Lactancia , Virulencia/genética , Genotipo , Útero , Cabras
16.
Int J Mol Sci ; 24(6)2023 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-36982944

RESUMEN

Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus (CoV) that causes lethal watery diarrhea in neonatal pigs and poses economic and public health burdens. Currently, there are no effective antiviral agents against PDCoV. Curcumin is the active ingredient extracted from the rhizome of turmeric, which has a potential pharmacological value because it exhibits antiviral properties against several viruses. Here, we described the antiviral effect of curcumin against PDCoV. At first, the potential relationships between the active ingredients and the diarrhea-related targets were predicted through a network pharmacology analysis. Twenty-three nodes and 38 edges were obtained using a PPI analysis of eight compound-targets. The action target genes were closely related to the inflammatory and immune related signaling pathways, such as the TNF signaling pathway, Jak-STAT signaling pathway, and so on. Moreover, IL-6, NR3C2, BCHE and PTGS2 were identified as the most likely targets of curcumin by binding energy and 3D protein-ligand complex analysis. Furthermore, curcumin inhibited PDCoV replication in LLC-PK1 cells at the time of infection in a dose-dependent way. In poly (I:C) pretreated LLC-PK1 cells, PDCoV reduced IFN-ß production via the RIG-I pathway to evade the host's antiviral innate immune response. Meanwhile, curcumin inhibited PDCoV-induced IFN-ß secretion by inhibiting the RIG-I pathway and reduced inflammation by inhibiting IRF3 or NF-κB protein expression. Our study provides a potential strategy for the use of curcumin in preventing diarrhea caused by PDCoV in piglets.


Asunto(s)
Coronavirus , Curcumina , Enfermedades de los Porcinos , Animales , Porcinos , Células LLC-PK1 , Curcumina/farmacología , Curcumina/metabolismo , Coronavirus/genética , Antivirales/farmacología , Antivirales/metabolismo , Diarrea
17.
Nature ; 537(7620): 417-421, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27501248

RESUMEN

Chronic viral infections are characterized by a state of CD8+ T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8+ T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8+ T cells. Here we identify a population of virus-specific CD8+ T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8+ T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8+ T-cell subset was characterized by a unique gene signature that was related to that of CD4+ T follicular helper (TFH) cells, CD8+ T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4+ TH1 cells and CD8+ terminal effectors. This CD8+ T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8+ T cells. These PD-1+CD8+ T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8+ T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8+ T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8+ T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.


Asunto(s)
Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/efectos de los fármacos , Inmunoterapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Animales , Antígenos CD28/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular , Proliferación Celular/efectos de los fármacos , Autorrenovación de las Células , Femenino , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/inmunología , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Coriomeningitis Linfocítica , Virus de la Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones , Receptor de Muerte Celular Programada 1/metabolismo , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo
18.
Cereb Cortex ; 31(7): 3551-3564, 2021 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-33774666

RESUMEN

In order to achieve optimal outcomes in an ever-changing environment, humans and animals generally manage their action control via either goal-directed action or habitual action. These two action strategies are thought to be encoded in distinct parallel circuits in the dorsal striatum, specifically, the posterior dorsomedial striatum (DMS) and the dorsolateral striatum (DLS), respectively. The striatum is primarily composed of two subtypes of medium spiny neurons (MSNs): the direct-pathway striatonigral and the indirect-pathway striatopallidal MSNs. MSN-subtype-specific synaptic plasticity in the DMS and the DLS has been revealed to underlie goal-directed action and habitual action, respectively. However, whether any MSN-subtype-specific synaptic plasticity in the DMS is associated with habitual action, and if so, whether the synaptic plasticity affects the formation of habitual action, are not known. This study demonstrates that postsynaptic depression in the excitatory synapses of the direct-pathway striatonigral MSNs in the DMS is formed after habit learning. Moreover, chemogenetically rescuing this depression compromises the acquisition, but not the expression, of habitual action. These findings reveal that an MSN-subtype-specific synaptic plasticity in the DMS affects habitual action and suggest that plasticity in the DMS as well as in the DLS contributes to the formation of habitual action.


Asunto(s)
Condicionamiento Operante/fisiología , Globo Pálido/fisiología , Hábitos , Depresión Sináptica a Largo Plazo/fisiología , Neostriado/fisiología , Neuronas/fisiología , Sustancia Negra/fisiología , Animales , Masculino , Ratones , Ratones Transgénicos , Vías Nerviosas/fisiología , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Técnicas de Placa-Clamp , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo
19.
Int J Mol Sci ; 23(9)2022 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-35563007

RESUMEN

The widespread prevalence of antimicrobial resistance has spawned the development of novel antimicrobial agents. Antimicrobial peptides (AMPs) have gained comprehensive attention as one of the major alternatives to antibiotics. However, low antibacterial activity and high-cost production have limited the applications of natural AMPs. In this study, we successfully expressed recombinant Zophobas atratus (Z. atratus) defensin for the first time. In order to increase the antimicrobial activity of peptide, we designed 5 analogues derived from Z. atratus defensin, Z-d13, Z-d14C, Z-d14CF, Z-d14CR and Z-d14CFR. Our results showed that Z-d14CFR (RGCRCNSKSFCVCR-NH2) exhibited a broad-spectrum antimicrobial activity to both Gram-positive bacteria and Gram-negative bacteria, including multidrug-resistant bacteria. It possessed less than 5% hemolysis and 10% cytotoxicity, even at a high concentration of 1 mg/mL. Antimicrobial mechanism studies indicated that Z-d14CFR performed antimicrobial effect via inhibiting biofilm formation, disrupting bacterial membrane integrity and inducing cellular contents release. Furthermore, Z-d14CFR showed a great therapeutic effect on the treatment of multidrug-resistant Escherichia coli (E. coli) infection by enhancing bacterial clearance, decreasing neutrophils infiltration and the expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) in a murine model of mastitis. Our findings suggest that Z-d14CFR could be a promising candidate against multidrug-resistant bacteria.


Asunto(s)
Antiinfecciosos , Defensinas , Mastitis , Animales , Antibacterianos/química , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antiinfecciosos/farmacología , Péptidos Antimicrobianos/farmacología , Bacterias , Biopelículas , Defensinas/farmacología , Modelos Animales de Enfermedad , Escherichia coli , Femenino , Mastitis/tratamiento farmacológico , Ratones , Pruebas de Sensibilidad Microbiana , Péptidos/farmacología
20.
J Physiol ; 598(20): 4643-4661, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32844405

RESUMEN

KEY POINTS: The Arg271Gln mutation of the glycine receptor (GlyR) causes hereditary hyperekplexia. This mutation dramatically compromises GlyR function; however, the underlying mechanism is not yet known. This study, by employing function and computation methods, proposes that charged residues (including the Arg residue) at the pore extracellular half from each of the five subunits of the homomeric α1 GlyR, create an electrostatic repulsive potential to widen the pore, thereby facilitating channel opening. This mechanism explains how the Arg271Gln mutation, in which the positively charged Arg residue is substituted by the neutral Gln residue, compromises GlyR function. This study furthers our understanding of the biophysical mechanism underlying the Arg271Gln mutation compromising GlyR function. ABSTRACT: The R271(19')Q mutation in the α1 subunit of the glycine receptor (GlyR) chloride channel causes hereditary hyperekplexia. This mutation dramatically compromises channel function; however, the underlying mechanism is not yet known. The R271 residue is located at the extracellular half of the channel pore. In this study, an Arg-scanning mutagenesis was performed at the pore extracellular half from the 262(10') to the 272(20') position on the background of the α1 GlyR carrying the hyperekplexia-causing mutation R271(19')Q. It was found that the placement of the Arg residue rescued channel function to an extent inversely correlated with the distance between the residue and the pore central axis (perpendicular to the plane of the lipid bilayer). Accordingly, it was hypothesized that the placed Arg residues from each of the five subunits of the homomeric α1 GlyR create an electrostatic repulsive potential to widen the pore, thereby facilitating channel opening. This hypothesis was quantitatively verified by theoretical computation via exploiting basic laws of electrostatics and thermodynamics, and further supported by more experimental findings that the placement of another positively charged Lys residue or even a negatively charged Asp residue also rescued channel function in the same manner. This study provides a novel mechanism via which charged residues in the pore region facilitate channel gating, not only for the disease-causing 19'R residue in the GlyR, but also potentially for charged residues in the same region of other ion channels.


Asunto(s)
Hiperekplexia , Receptores de Glicina , Humanos , Rigidez Muscular , Receptores de Glicina/genética , Receptores de Glicina/metabolismo , Electricidad Estática , Transmisión Sináptica
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