Modulation of let-7 miRNAs controls the differentiation of effector CD8 T cells

Wells, Alexandria; Daniels, Keith A.; Angelou, Constance C; Fagerberg, Eric; Burnside, Amy; Markstein, Michele; Alfandari, Dominique; Welsh, Raymond M.; Pobezinskaya, E. L.; Pobezinsky, Leonid A

doi:10.7554/elife.26398

Cited by 75 publications

(84 citation statements)

References 83 publications

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“…The effector program (e.g., IFNγ and granzymes) observed in ex vivo fetal γδ thymocytes was HSPC- and Lin28b-dependent. Since these effector molecules do not contain a let7 motif within the 3′ untranslated region of their mRNA sequences (where typically miRNA-binding sites are found; Wells et al, 2017), it is more likely that the Lin28b/let7-dependency is indirect. One possibility is via the innate lymphocyte transcription factor PLZF (ZBTB16), which was highly expressed by ex vivo fetal γδ thymocytes and fetal HSCP-derived γδ T cells and showed increased expression upon Lin28b overexpression.…”

Section: Discussionmentioning

confidence: 99%

The human fetal thymus generates invariant effector γδ T cells

Tieppo

Papadopoulou

Gatti

et al. 2019

Journal of Experimental Medicine

137

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In the mouse thymus, invariant γδ T cells are generated at well-defined times during development and acquire effector functions before exiting the thymus. However, whether such thymic programming and age-dependent generation of invariant γδ T cells occur in humans is not known. Here we found that, unlike postnatal γδ thymocytes, human fetal γδ thymocytes were functionally programmed (e.g., IFNγ, granzymes) and expressed low levels of terminal deoxynucleotidyl transferase (TdT). This low level of TdT resulted in a low number of N nucleotide insertions in the complementarity-determining region-3 (CDR3) of their TCR repertoire, allowing the usage of short homology repeats within the germline-encoded VDJ segments to generate invariant/public cytomegalovirus-reactive CDR3 sequences (TRGV8-TRJP1-CATWDTTGWFKIF, TRDV2-TRDD3-CACDTGGY, and TRDV1-TRDD3-CALGELGD). Furthermore, both the generation of invariant TCRs and the intrathymic acquisition of effector functions were due to an intrinsic property of fetal hematopoietic stem and precursor cells (HSPCs) caused by high expression of the RNA-binding protein Lin28b. In conclusion, our data indicate that the human fetal thymus generates, in an HSPC/Lin28b-dependent manner, invariant γδ T cells with programmed effector functions.

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Section: Discussionmentioning

confidence: 99%

The human fetal thymus generates invariant effector γδ T cells

Tieppo

Papadopoulou

Gatti

et al. 2019

Journal of Experimental Medicine

137

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“…However, the lack of vimentin expression in SEs may suggest that these accounted for the vast majority of the miRNAs that were expressed, of which 15 were common to all the analyzed samples independently of infection status or interval after EAV infection. The top five miRNAs expressed in SEs included members of the let-7 family, mir-21 and mir10b, which have been demonstrated to play an active role in the modulation of several immune pathways, including modulation of T cell activation, NK cell function, IL-10 production by CD4 ϩ T lymphocytes, CD8 ϩ effector T lymphocyte differentiation, and NF-B pathway, among others (69)(70)(71)(72)(73)(74). From a confirmative viewpoint, these findings are similar to those reported for human SEs (34), suggesting that these miRNAs can be involved in similar modulatory processes in both species.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of MicroRNA eca-mir-128 in Seminal Exosomes and Enhanced Expression of CXCL16 in the Stallion Reproductive Tract Are Associated with Long-Term Persistence of Equine Arteritis Virus

Carossino

Dini

Kalbfleisch

et al. 2018

J Virol

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Equine arteritis virus (EAV) can establish long-term persistent infection in the reproductive tract of stallions and is shed in the semen. Previous studies showed that long-term persistence is associated with a specific allele of the gene () and that persistent infection is maintained despite the presence of a local inflammatory and humoral and mucosal antibody responses. In this study, we demonstrated that equine seminal exosomes (SEs) are enriched in a small subset of microRNAs (miRNAs). Most importantly, we demonstrated that long-term EAV persistence is associated with the downregulation of an SE-associated miRNA (eca-mir-128) and with an enhanced expression of CXCL16 in the reproductive tract, a putative target of eca-mir-128. The findings presented here suggest that SE eca-mir-128 is implicated in the regulation of the CXCL16/CXCR6 axis in the reproductive tract of persistently infected stallions, a chemokine axis strongly implicated in EAV persistence. This is a novel finding and warrants further investigation to identify its specific mechanism in modulating the CXCL16/CXCR6 axis in the reproductive tract of the EAV long-term carrier stallion. Equine arteritis virus (EAV) has the ability to establish long-term persistent infection in the stallion reproductive tract and to be shed in semen, which jeopardizes its worldwide control. Currently, the molecular mechanisms of viral persistence are being unraveled, and these are essential for the development of effective therapeutics to eliminate persistent infection. Recently, it has been determined that long-term persistence is associated with a specific allele of the gene () and is maintained despite induction of local inflammatory, humoral, and mucosal antibody responses. This study demonstrated that long-term persistence is associated with the downregulation of seminal exosome miRNA eca-mir-128 and enhanced expression of its putative target, CXCL16, in the reproductive tract. For the first time, this study suggests complex interactions between eca-mir-128 and cellular elements at the site of EAV persistence and implicates this miRNA in the regulation of the CXCL16/CXCR6 axis in the reproductive tract during long-term persistence.

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“…Peptides bound to MHC molecules serve as recognizing fragments of antigen for the TCR. Here it is worth noting the recently defined dual role of miRNA in maintenance of the naive phenotype of CD8 T cells or clonal expansion, where modulation of Let-7 miRNAs levels is required (Wells et al, 2017). Here it is worth noting the recently defined dual role of miRNA in maintenance of the naive phenotype of CD8 T cells or clonal expansion, where modulation of Let-7 miRNAs levels is required (Wells et al, 2017).…”

Section: Cell-mediated Immune Response(s)mentioning

confidence: 99%

“…Emerging systems for measuring miRNA activity during immune activation revealed the complex network of genes that may be simultaneously targeted by miRNAs to tune distinct cell fate decisions (Wells et al, 2017). In the periphery, regulatory T cells (Tregs) play a key role in restraining the activity of mature B and T (Th1, Th2 and Th17) cells, and preserving tolerance mechanism(s).…”

Section: General Information On Immunoregulatory Processes Associatedmentioning

confidence: 99%

Literature review of baseline information on non‐coding RNA (ncRNA) to support the risk assessment of ncRNA‐based genetically modified plants for food and feed

Dávalos

Henriques

Latasa

et al. 2019

EFS3

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This report is the outcome of an EFSA procurement (NP/EFSA/GMO/2016/01) reviewing relevant scientific information on ncRNA and on RNA interference (RNAi) that could support the food and feed risk assessment of ncRNA-based genetically modified (GM) plants. Information was retrieved through key words and key questions covering the stability and degradation of ncRNAs after oral ingestion, the passage of ncRNAs from food and feed to human and animal organs and tissues via the gastrointestinal tract and other barriers, as well as the potential effects on the gastrointestinal tract, the immune system or the entire organism. Full description of the strategy used for the literature search and for studies selection is provided and the number of retrieved publications is reported. This report is divided into four parts discussing the kinetics of exogenous ncRNAs in humans and animals, with focus on ingested ncRNAs (Part 1); the possible effects of ncRNAs on the gastrointestinal tract (Part 2), systemically (Part 3) and on the immune system (Part 4). This report suggests that some plant ncRNAs (e.g miRNAs and siRNAs) show higher stability as compared to other ncRNAs due to peculiar chemical characteristics (2'-O-methylation at 3' end). However, ingested or administered ncRNA must overcome many extracellular and cellular barriers to reach the intended target tissue or functional location in sufficient amount to exert any biological effect. Literature data indicate that chemically unmodified and unformulated ncRNAs exhibit very low stability in the gastrointestinal tract and in biological fluids and, in general, do not elicit major biological effects. This report also provides an overview of the RNA content in plant-derived foods and diets and discusses the controversies on the presence of dietary exogenous RNAs in the biological fluids of humans and animals and their effects. Finally, gaps in the scientific literature are highlighted and recommendations provided.

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Modulation of let-7 miRNAs controls the differentiation of effector CD8 T cells

Cited by 75 publications

References 83 publications

The human fetal thymus generates invariant effector γδ T cells

The human fetal thymus generates invariant effector γδ T cells

Downregulation of MicroRNA eca-mir-128 in Seminal Exosomes and Enhanced Expression of CXCL16 in the Stallion Reproductive Tract Are Associated with Long-Term Persistence of Equine Arteritis Virus

Literature review of baseline information on non‐coding RNA (ncRNA) to support the risk assessment of ncRNA‐based genetically modified plants for food and feed

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