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1.
Cell Immunol ; 395-396: 104797, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38157646

RESUMO

Vγ9Vδ2 T lymphocytes are programmed for broad antimicrobial responses with rapid production of Th1 cytokines even before birth, and thus thought to play key roles against pathogens in infants. The process regulating Vδ2 cell acquisition of cytotoxic potential shortly after birth remains understudied. We observed that perforin production in cord blood Vδ2 cells correlates with phenotypes defined by the concomitant assessment of PD-1 and CD56. Bulk RNA sequencing of sorted Vδ2 cell fractions indicated that transcripts related to cytotoxic activity and NK function are enriched in the subset with the highest proportion of perforin+ cells. Among differentially expressed transcripts, IRF8, previously linked to CD8 T cell effector differentiation and NK maturation, has the potential to mediate Vδ2 cell differentiation towards cytotoxic effectors. Our current and past results support the hypothesis that distinct mechanisms regulate Vδ2 cell cytotoxic function before and after birth, possibly linked to different levels of microbial exposure.


Assuntos
Antígeno CD56 , Linfócitos T CD8-Positivos , Citotoxicidade Imunológica , Receptor de Morte Celular Programada 1 , Receptores de Antígenos de Linfócitos T gama-delta , Subpopulações de Linfócitos T , Humanos , Linfócitos T CD8-Positivos/imunologia , Citocinas/metabolismo , Sangue Fetal , Perforina/genética , Perforina/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/imunologia , Antígeno CD56/metabolismo
2.
Cell Immunol ; 359: 104244, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33248366

RESUMO

Human Vγ9Vδ2 T cells respond to several diverse pathogens by sensing microbial cholesterol intermediates. Unlike CD4 T cells, they are poised for rapid Th1-like responses even before birth, which allows them to play a key role in the first line of defense against pathogens in early life. However, their regulation and functional maturation during infancy (in particular the acquisition of cytotoxic potential) remain understudied. We thus characterized their responses to cholesterol intermediates and Bacille Calmette-Guérin in a cohort of African neonates and 12-month-old infants. Infant Vδ2 lymphocytes exhibited intermediate or adult-like expression of markers associated with differentiation or function, intermediate proliferative responses, and adult-like cytotoxic potential. The enhancement of Vδ2 cell cytotoxic potential coincided with decreasing PD-1 and increasing NKG2A expression. Our results are consistent with the hypothesis that switching from a PD-1+ to a NKG2A+ phenotype during infancy indicates a shift in mechanisms regulating Vδ2 T cell function.


Assuntos
Sangue Fetal/citologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Adulto , Fatores Etários , Diferenciação Celular/fisiologia , Células Cultivadas , Cordocentese , Feminino , Expressão Gênica/genética , Humanos , Lactente , Recém-Nascido , Interferon gama/metabolismo , Ativação Linfocitária/imunologia , Malaui/epidemiologia , Masculino , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptores de Antígenos de Linfócitos T gama-delta/genética , Linfócitos T/imunologia
3.
Malar J ; 18(1): 84, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30885193

RESUMO

BACKGROUND: Current World Health Organization guidelines for conducting anti-malarial drug efficacy clinical trials recommend genotyping Plasmodium falciparum genes msp1 and msp2 to distinguish recrudescence from reinfection. A more recently developed potential alternative to this method is a molecular genotyping assay based on a panel of 24 single nucleotide polymorphism (SNP) markers. METHODS: Performance parameters of these two genotyping methods were compared using data from two recently completed drug efficacy trials. Blood samples from two anti-malarial therapeutic trials were analysed by both msp genotyping and the 24 SNP assay. Additionally, to conserve time and resources, the statistical program R was used to select the most informative SNPs for a set of unrelated Malawian samples to develop a truncated SNP-based assay for the region surrounding Blantyre, Malawi. The ability of this truncated assay to distinguish reinfection from recrudescence when compared to the full 24 SNP assay was then analysed using data from the therapeutic trials. RESULTS: A total of 360 samples were analysed; 66 for concordance of msp and SNP barcoding methodologies, and 294 for assessing the most informative of the 24 SNP markers. SNP genotyping performed comparably to msp genotyping, with only one case of disagreement among the 50 interpretable results, where the SNP assay identified the sample as reinfection and the msp typing as recrudescence. Furthermore, SNP typing was more robust; only 6% of samples were uninterpretable by SNP typing, compared to 19.7% when msp genotyping was used. For discriminating reinfection from recrudescence, a truncated 6 SNP assay was found to perform at 95.1% the accuracy of the full 24 SNP bar code. CONCLUSIONS: The use of SNP analysis has similar sensitivity to the standard msp genotyping in determining recrudescence from reinfection. Although more expensive, SNP typing is faster and less work intensive. Limiting the assay to those SNPs most informative in the geographical region of interest may further decrease the workload and the cost, making this technique a feasible and affordable alternative in drug efficacy trials.


Assuntos
Antígenos de Protozoários/genética , Técnicas de Genotipagem/métodos , Malária Falciparum/diagnóstico , Malária Falciparum/parasitologia , Proteína 1 de Superfície de Merozoito/genética , Plasmodium falciparum/classificação , Polimorfismo de Nucleotídeo Único , Proteínas de Protozoários/genética , Pré-Escolar , Ensaios Clínicos como Assunto , Feminino , Genótipo , Humanos , Lactente , Malaui , Masculino , Plasmodium falciparum/genética , Plasmodium falciparum/isolamento & purificação , Recidiva , Sensibilidade e Especificidade , Fatores de Tempo
4.
J Immunol ; 197(5): 1884-92, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27474072

RESUMO

A successful pregnancy depends on the maintenance of tolerance at the fetal-maternal interface; strong inflammation in the placental bed is generally associated with adverse fetal outcomes. Among the mechanisms that foster tolerance and limit inflammation, the fetal immune system favors Th2 or regulatory responses over Th1 responses. The unintended consequence of this functional program is high susceptibility to infections. Human Vδ2 T cells mount innate-like responses to a broad range of microorganisms and are poised for Th1 responses before birth. In infants they likely play a key role in protection against pathogens by exerting early Th1 effector functions, improving function of other innate cells, and promoting Th1 polarization of adaptive responses. However, their propensity to release Th1 mediators may require careful regulation during fetal life to avoid exaggerated proinflammatory responses. We investigated molecules with the potential to act as a rheostat for fetal Vδ2 cells. Programmed death 1 (PD1) is a negative regulator of T cell responses and a determinant of tolerance, particularly at the fetal-maternal interface. Neonatal Vδ2 cells upregulate PD1 shortly after activation and, unlike their adult counterparts, express this molecule for at least 28 d. Engagement of PD1 by one of its ligands, PDL1, effectively dampens TCR-mediated responses (TNF-α production and degranulation) by neonatal Vδ2 cells and may thus help maintain their activity within safe limits. PD1 expression by neonatal Vδ2 cells is inversely associated with promoter DNA methylation. Prolonged PD1 expression may be part of a functional program to control Vδ2 cell inflammatory responses during fetal life.


Assuntos
Epigênese Genética , Regulação da Expressão Gênica , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Antígeno B7-H1/imunologia , Metilação de DNA , Feminino , Desenvolvimento Fetal , Humanos , Tolerância Imunológica , Recém-Nascido , Inflamação/imunologia , Ativação Linfocitária , Gravidez , Regiões Promotoras Genéticas , Células Th1/imunologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia
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