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1.
Immunity ; 54(11): 2497-2513.e9, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34562377

RESUMO

Innate-like T cell populations expressing conserved TCRs play critical roles in immunity through diverse developmentally acquired effector functions. Focusing on the prototypical lineage of invariant natural killer T (iNKT) cells, we sought to dissect the mechanisms and timing of fate decisions and functional effector differentiation. Utilizing induced expression of the semi-invariant NKT cell TCR on double positive thymocytes, an initially highly synchronous wave of iNKT cell development was triggered by brief homogeneous TCR signaling. After reaching a uniform progenitor state characterized by IL-4 production potential and proliferation, effector subsets emerged simultaneously, but then diverged toward different fates. While NKT17 specification was quickly completed, NKT1 cells slowly differentiated and expanded. NKT2 cells resembled maturing progenitors, which gradually diminished in numbers. Thus, iNKT subset diversification occurs in dividing progenitor cells without acute TCR input but utilizes multiple active cytokine signaling pathways. These data imply a two-step model of iNKT effector differentiation.


Assuntos
Citocinas/metabolismo , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Biomarcadores , Diferenciação Celular/imunologia , Ativação Linfocitária/imunologia
2.
Biochem Biophys Res Commun ; 538: 204-210, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33220925

RESUMO

T-cells play key roles in immunity to COVID-19 as well as the development of severe disease. T-cell immunity to COVID-19 is mediated through differentiated CD4+ T-cells and cytotoxic CD8+ T-cells, although their differentiation is often atypical and ambiguous in COVID-19 and single cell dynamics of key genes need to be characterized. Notably, T-cells are dysregulated in severe COVID-19 patients, although their molecular features are still yet to be fully revealed. Importantly, it is not clear which T-cell activities are beneficial and protective and which ones can contribute to the development of severe COVID-19. In this article, we examine the latest evidence and discuss the key features of T-cell responses in COVID-19, showing how T-cells are dysregulated in severe COVID-19 patients. Particularly, we highlight the impairment of FOXP3 induction in CD4+ T-cells and how the impaired FOXP3 expression can lead to the differentiation of abnormally activated (hyperactivated) T-cells and the dysregulated T-cell responses in severe patients. Furthermore, we characterise the feature of hyperactivated T-cells, showing their potential contribution to T-cell dysregulation and immune-mediated tissue destruction (immunopathology) in COVID-19.


Assuntos
Linfócitos T CD4-Positivos/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Linfócitos T Citotóxicos/imunologia , COVID-19/patologia , Citocinas/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Ativação Linfocitária
3.
Front Immunol ; 11: 589380, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33178221

RESUMO

Severe COVID-19 patients show various immunological abnormalities including T-cell reduction and cytokine release syndrome, which can be fatal and is a major concern of the pandemic. However, it is poorly understood how T-cell dysregulation can contribute to the pathogenesis of severe COVID-19. Here we show single cell-level mechanisms for T-cell dysregulation in severe COVID-19, demonstrating new pathogenetic mechanisms of T-cell activation and differentiation underlying severe COVID-19. By in silico sorting CD4+ T-cells from a single cell RNA-seq dataset, we found that CD4+ T-cells were highly activated and showed unique differentiation pathways in the lung of severe COVID-19 patients. Notably, those T-cells in severe COVID-19 patients highly expressed immunoregulatory receptors and CD25, whilst repressing the expression of FOXP3. Furthermore, we show that CD25+ hyperactivated T-cells differentiate into multiple helper T-cell lineages, showing multifaceted effector T-cells with Th1 and Th2 characteristics. Lastly, we show that CD25-expressing hyperactivated T-cells produce the protease Furin, which facilitates the viral entry of SARS-CoV-2. Collectively, CD4+ T-cells from severe COVID-19 patients are hyperactivated and FOXP3-mediated negative feedback mechanisms are impaired in the lung, which may promote immunopathology. Therefore, our study proposes a new model of T-cell hyperactivation and paralysis that drives immunopathology in severe COVID-19.


Assuntos
COVID-19/imunologia , Ativação Linfocitária/imunologia , Paralisia/imunologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Análise de Célula Única/métodos , Linfócitos T Reguladores/imunologia , COVID-19/virologia , Bases de Dados Genéticas , Fatores de Transcrição Forkhead/metabolismo , Furina/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , RNA-Seq , Receptores de Antígenos de Linfócitos T/metabolismo , Transcriptoma , Internalização do Vírus
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