MicroRNA-155 Regulates MAIT1 and MAIT17 Cell Differentiation

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that develop in the thymus through three maturation stages to acquire effector function and differentiate into MAIT1 (T-bet+) and MAIT17 (RORγt+) subsets. Upon activation, MAIT cells release IFN-γ and IL-17, which modulate a broad spectrum of diseases. Recent studies indicate defective MAIT cell development in microRNA deficient mice, however, few individual miRNAs have been identified to regulate MAIT cells. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affect some immune cell development, but its role in MAIT cell development remains unclear. To address whether miR-155 is required for MAIT cell development, we performed gain-of-function and loss-of-function studies. We first generated a CD4Cre.miR-155 knock-in mouse model, in which miR-155 is over-expressed in the T cell lineage. We found that overexpression of miR-155 significantly reduced numbers and frequencies of MAIT cells in all immune organs and lungs and blocked thymic MAIT cell maturation through downregulating PLZF expression. Strikingly, upregulated miR-155 promoted MAIT1 differentiation and blocked MAIT17 differentiation, and timely inducible expression of miR-155 functionally inhibited peripheral MAIT cells secreting IL-17. miR-155 overexpression also increased CD4–CD8+ subset and decreased CD4–CD8– subset of MAIT cells. We further analyzed MAIT cells in conventional miR-155 knockout mice and found that lack of miR-155 also promoted MAIT1 differentiation and blocked MAIT17 differentiation but without alteration of their overall frequency, maturation and function. Overall, our results indicate that adequate miR-155 expression is required for normal MAIT1 and MAIT17 cell development and function.

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MicroRNA Regulation of Immune Cell Development and Function

Blood ◽

10.1182/blood.v116.21.sci-31.sci-31 ◽

2010 ◽

Vol 116 (21) ◽

pp. SCI-31-SCI-31

Author(s):

Dinesh S. Rao

Keyword(s):

Immune Cell ◽

Conflicts Of Interest ◽

Myeloid Cell ◽

Cell Development ◽

Dependent Manner ◽

Loss Of Function ◽

Nf Kappa B ◽

Hematopoietic Development ◽

Myeloid Development ◽

And Function

Abstract Abstract SCI-31 The NF-kappa B pathway is a central mediator of inflammation and plays an important role in myeloid cell development. During activation of macrophages by LPS, three microRNAs (miRNAs) were initially identified as being upregulated in an NF-kappa B dependent manner. Subsequent efforts to characterize two of these miRNAs, namely miR-155 and miR-146a, have revealed important roles not only in inflammation but also in hematopoietic development. Curiously, these two miRNAs seem to play opposing roles in promoting immune cell and progenitor proliferation, and the phenotypes induced in gain and loss-of-function contexts will be discussed in detail. Specifically, miR-155 overexpression and miR-146a deficiency lead to myeloid proliferations with pathologic consequences. These differential roles are largely explained by the targets of these microRNAs, which include signal transduction regulators: SHIP1 and SOCS1 in the case of miR-155, and TRAF6 and IRAK1 in the case of miR-146a. The roles of these miRNAs as effector and feedback regulator of the NF-kappa B pathway, respectively, will be discussed in the context of myeloid development. More broadly, these studies, as well as studies of miRNAs in B-cell development, have revealed that understanding miRNA roles in these processes will illuminate new aspects of biology and pathology. For example, the regulation of hematopoietic development by these miRNAs has revealed important interconnections between pathways that previously may have been considered disparate. Moreover, these studies have begun to underscore the importance of identifying specific targets of a miRNA in a given physiologic or pathologic context. Disclosures: No relevant conflicts of interest to declare.

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Pathophysiology of acute respiratory syndrome coronavirus 2 infection: a systematic literature review to inform EULAR points to consider

RMD Open ◽

10.1136/rmdopen-2020-001549 ◽

2021 ◽

Vol 7 (1) ◽

pp. e001549 ◽

Cited By ~ 1

Author(s):

Aurélie Najm ◽

Alessia Alunno ◽

Xavier Mariette ◽

Benjamin Terrier ◽

Gabriele De Marco ◽

...

Keyword(s):

Literature Review ◽

Systematic Literature Review ◽

Immune Cell ◽

Severe Disease ◽

Cell Phenotype ◽

Loss Of Function ◽

Humoral And Cellular Immunity ◽

Host Immune Responses ◽

Disease Spectrum ◽

And Function

BackgroundThe SARS-CoV-2 pandemic is a global health problem. Beside the specific pathogenic effect of SARS-CoV-2, incompletely understood deleterious and aberrant host immune responses play critical roles in severe disease. Our objective was to summarise the available information on the pathophysiology of COVID-19.MethodsTwo reviewers independently identified eligible studies according to the following PICO framework: P (population): patients with SARS-CoV-2 infection; I (intervention): any intervention/no intervention; C (comparator): any comparator; O (outcome) any clinical or serological outcome including but not limited to immune cell phenotype and function and serum cytokine concentration.ResultsOf the 55 496 records yielded, 84 articles were eligible for inclusion according to question-specific research criteria. Proinflammatory cytokine expression, including interleukin-6 (IL-6), was increased, especially in severe COVID-19, although not as high as other states with severe systemic inflammation. The myeloid and lymphoid compartments were differentially affected by SARS-CoV-2 infection depending on disease phenotype. Failure to maintain high interferon (IFN) levels was characteristic of severe forms of COVID-19 and could be related to loss-of-function mutations in the IFN pathway and/or the presence of anti-IFN antibodies. Antibody response to SARS-CoV-2 infection showed a high variability across individuals and disease spectrum. Multiparametric algorithms showed variable diagnostic performances in predicting survival, hospitalisation, disease progression or severity, and mortality.ConclusionsSARS-CoV-2 infection affects both humoral and cellular immunity depending on both disease severity and individual parameters. This systematic literature review informed the EULAR ‘points to consider’ on COVID-19 pathophysiology and immunomodulatory therapies.

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The UNC-45 chaperone mediates sarcomere assembly through myosin degradation in Caenorhabditis elegans

The Journal of Cell Biology ◽

10.1083/jcb.200607084 ◽

2007 ◽

Vol 177 (2) ◽

pp. 205-210 ◽

Cited By ~ 61

Author(s):

Megan L. Landsverk ◽

Shumin Li ◽

Alex H. Hutagalung ◽

Ayaz Najafov ◽

Thorsten Hoppe ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Proteasome Inhibition ◽

Thick Filament ◽

Ubiquitin Proteasome System ◽

Loss Of Function ◽

Cellular Processes ◽

Ubiquitin Proteasome ◽

Myosin Motors ◽

And Function ◽

Sarcomere Assembly

Myosin motors are central to diverse cellular processes in eukaryotes. Homologues of the myosin chaperone UNC-45 have been implicated in the assembly and function of myosin-containing structures in organisms from fungi to humans. In muscle, the assembly of sarcomeric myosin is regulated to produce stable, uniform thick filaments. Loss-of-function mutations in Caenorhabditis elegans UNC-45 lead to decreased muscle myosin accumulation and defective thick filament assembly, resulting in paralyzed animals. We report that transgenic worms overexpressing UNC-45 also display defects in myosin assembly, with decreased myosin content and a mild paralysis phenotype. We find that the reduced myosin accumulation is the result of degradation through the ubiquitin/proteasome system. Partial proteasome inhibition is able to restore myosin protein and worm motility to nearly wild-type levels. These findings suggest a mechanism in which UNC-45–related proteins may contribute to the degradation of myosin in conditions such as heart failure and muscle wasting.

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bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice.

Journal of Experimental Medicine ◽

10.1084/jem.183.2.381 ◽

1996 ◽

Vol 183 (2) ◽

pp. 381-391 ◽

Cited By ~ 140

Author(s):

D A Grillot ◽

R Merino ◽

J C Pena ◽

W C Fanslow ◽

F D Finkelman ◽

...

Keyword(s):

B Cells ◽

Transgenic Mice ◽

B Cell ◽

Cell Lineage ◽

Cell Development ◽

B Cell Development ◽

Immunoglobulin M ◽

Protective Mechanism ◽

And Function ◽

Peripheral B Cells

We have assessed during B cell development, the regulation and function of bcl-x, a member of the bcl-2 family of apoptosis regulatory genes. Here we show that Bcl-xL, a product of bcl-x, is expressed in pre-B cells but downregulated at the immature and mature stages of B cell development. Bcl-xL but not Bcl-2 is rapidly induced in peripheral B cells upon surface immunoglobulin M (IgM) cross-linking, CD40 signaling, or LPS stimulation. Transgenic mice that overexpressed Bcl-xL within the B cell lineage exhibited marked accumulation of peripheral B cells in lymphoid organs and enhanced survival of developing and mature B cells. B cell survival was further increased by simultaneous expression of bcl-xL and bcl-2 transgenes. These studies demonstrate that Bcl-2 and Bcl-xL are regulated differentially during B cell development and activation of mature B cells. Induction of Bcl-xL after signaling through surface IgM and CD40 appears to provide mature B cells with an additional protective mechanism against apoptotic signals associated with antigen-induced activation and proliferation.

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Dicer in immune cell development and function

Immunological Investigations ◽

10.3109/08820139.2013.863557 ◽

2013 ◽

Vol 43 (2) ◽

pp. 182-195 ◽

Cited By ~ 13

Author(s):

Anand S. Devasthanam ◽

Thomas B. Tomasi

Keyword(s):

Immune Cell ◽

Cell Development ◽

And Function

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Outcome of SARS-CoV-2 infection linked to MAIT cell activation and cytotoxicity: evidence for an IL-18 dependent mechanism

10.1101/2020.08.31.20185082 ◽

2020 ◽

Cited By ~ 4

Author(s):

Héloïse Flament ◽

Matthieu Rouland ◽

Lucie Beaudoin ◽

Amine Toubal ◽

Léo Bertrand ◽

...

Keyword(s):

Disease Severity ◽

Cell Activation ◽

Viral Infections ◽

Immune Cell ◽

Dependent Manner ◽

Mait Cells ◽

Inflammatory Phase ◽

Immune System Dysfunction ◽

Cell Counts ◽

Mait Cell

Immune system dysfunction is paramount in Coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in a cohort of 182 patients including patients at various stages of disease activity. A profound decrease of MAIT cell counts in blood of critically ill patients was observed. These cells showed a strongly activated and cytotoxic phenotype that positively correlated with circulating pro-inflammatory cytokines, notably IL-18. MAIT cell alterations markedly correlated with disease severity and patient mortality. SARS-CoV-2-infected macrophages activated MAIT cells in a cytokine-dependent manner involving an IFNα-dependent early phase and an IL-18-induced later phase. Therefore, altered MAIT cell phenotypes represent valuable biomarkers of disease severity and their therapeutic manipulation might prevent the inflammatory phase involved in COVID-19 aggravation.

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MicroRNA-155 Controls iNKT Cell Development and Lineage Differentiation by Coordinating Multiple Regulating Pathways

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.619220 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jie Wang ◽

Kai Li ◽

Xilin Zhang ◽

Guihua Li ◽

Tingting Liu ◽

...

Keyword(s):

T Cell ◽

Signaling Pathways ◽

T Cell Development ◽

Cell Lineage ◽

Cd8 T Cell ◽

Nkt Cells ◽

Cell Development ◽

Nkt Cell ◽

Cellular Processes ◽

Lineage Differentiation

The development of invariant natural killer T (iNKT) cells requires a well-attuned set of transcription factors, but how these factors are regulated and coordinated remains poorly understood. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affects cell development and homeostasis. Here, we found that miR-155 was highly expressed in early iNKT cells upon thymic selection, and then its expression is gradually downregulated during iNKT cell development. However, the mice with miR-155 germline deletion had normal iNKT cell development. To address if downregulated miR-155 is required for iNKT cell development, we made a CD4Cre.miR-155 knock-in (KI) mouse model with miR-155 conditional overexpression in the T cell lineage. Upregulated miR-155 led to interruption of iNKT cell development, diminished iNKT17 and iNKT1 cells, augmented iNKT2 cells, and these defects were cell intrinsic. Furthermore, defective iNKT cells in miR-155KI mice resulted in the secondary innate-like CD8 T cell development. Mechanistically, miR-155 modulated multiple targets and signaling pathways to fine tune iNKT cell development. MiR-155 modulated Jarid2, a critical component of a histone modification complex, and Tab2, the upstream activation kinase complex component of NF-κB, which function additively in iNKT development and in promoting balanced iNKT1/iNKT2 differentiation. In addition, miR-155 also targeted Rictor, a signature component of mTORC2 that controls iNKT17 differentiation. Taken together, our results indicate that miR-155 serves as a key epigenetic regulator, coordinating multiple signaling pathways and transcriptional programs to precisely regulate iNKT cell development and functional lineage, as well as secondary innate CD8 T cell development.

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