MicroRNA miR-181—A Rheostat for TCR Signaling in Thymic Selection and Peripheral T-Cell Function

Grewers, Zoe; Krueger, Andreas

doi:10.3390/ijms21176200

Cited by 19 publications

(16 citation statements)

References 94 publications

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“…Generally, regulatory impacts of several miR species on TCR signaling in T-cell physiology have been described. AGO2 itself can be subject to TCR-triggered proteasomal degradation (27,28). Interestingly, we noted increased AGO2 protein levels upon TCR stimulation in pan-CD3 + T-cells of one healthy donor and one T-PLL patient.…”

Section: Discussionmentioning

confidence: 72%

Noncanonical Function of AGO2 Augments T-cell Receptor Signaling in T-cell Prolymphocytic Leukemia

et al. 2022

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T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-refractory T-cell malignancy with limited therapeutic options and a poor prognosis. Current disease concepts implicate TCL1A oncogene-mediated enhanced T-cell receptor (TCR) signaling and aberrant DNA repair as central perturbed pathways. We discovered that recurrent gains on chromosome 8q more frequently involve the AGO2 gene than the adjacent MYC locus as the affected minimally amplified genomic region. AGO2 has been understood as a pro-tumorigenic key regulator of microRNA (miR) processing. In primary tumor material and cell line models, AGO2 overrepresentation associated (i) with higher disease burden, (ii) with enhanced in vitro viability and growth of leukemic T-cells, and (iii) with miR-omes and transcriptomes that highlight altered survival signaling, abrogated cell cycle control, and defective DNA damage responses. Moreover, AGO2 elicited immediate, rather than non-RNA mediated, effects in leukemic T-cells. Systems of genetically modulated AGO2 revealed that it enhances TCR signaling, particularly at the level of ZAP70, PLCγ1, and LAT kinase phospho-activation. In global mass-spectrometric analyses, AGO2 interacted with a unique set of partners in a TCR-stimulated context, including the TCR kinases LCK and ZAP70, forming membranous protein complexes. Models of their three-dimensional structure also suggested that AGO2 undergoes post-transcriptional modi-fications by LCK. This novel TCR-associated non-canonical function of AGO2 represents, in addition to TCL1A-mediated TCR signal augmentation, another enhancer mechanism of this important deregulated growth pathway in T-PLL. These findings further emphasize TCR signaling intermediates as candidates for therapeutic targeting.

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Section: Discussionmentioning

confidence: 72%

Noncanonical Function of AGO2 Augments T-cell Receptor Signaling in T-cell Prolymphocytic Leukemia

et al. 2022

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“…Moreover, previous research found that miR-181 expression in vivo led to substantial increases in both B-lymphoid (CD19 + ) cell and cytotoxic T-cell (CD8 + ) development in the thymus ( 46 ). Members of the miR-181 family have been shown to be dynamically regulated depend on the T-cell activation stage ( 15 ). During B. suis infection, miR-181a-5p expression was induced in porcine and murine macrophages, suggesting that miR-181a-5p may be involved in adaptive immunity ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

“…In Brucella -infected macrophages, the downregulation of miR-21-5p reduced IL-10 gene expression and increased the expressions of GBP5 and IL-12, thus inhibiting Brucella intracellular growth ( 13 , 14 ). The miR-181 family has been proven to be dynamically regulated during T-cell development and activation ( 15 ). During the B. suis 1330 infection, miR-181a-5p expression was induced in porcine and murine macrophages, suggesting that miR-181a-5p may be involved in adaptive immunity ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Three Novel miRNAs in the Lymph Nodes of Sheep Immunized With the Brucella suis Strain 2 Vaccine

et al. 2022

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Ovine and caprine brucellosis, both caused by Brucella melitensis, lead to substantial economic losses in the animal industry and health problems in human populations. Brucella suis strain 2 (B.suis S2), as a live attenuated vaccine, is used extensively in China to prevent brucellosis. It has been proven that microRNA (miRNAs) are involved in the immunopathogenesis of brucellosis; however, the miRNA-driven mechanism of immune response to B.suis S2 in vivo remains unknown. To determine which new miRNAs are involved in the host immune response to B.suis S2 and elucidate the function of these miRNAs, we performed a comprehensive analysis of miRNA expression profiles in sheep immunized with B.suis S2 using the high-throughput sequencing approach. The submandibular lymphatic nodes from sheep seropositive for Brucella were collected at 7, 14, 21, 30, 60 and 90 days post-immunization. MiRNA sequencing analysis revealed that 282 differentially expressed miRNAs (|log2 fold-change |>0.5 and p < 0.05) were significantly enriched in the immune pathways, including the NF-kappa B signaling pathway, B cell receptor signaling pathway, p53 signaling pathway and complement and coagulation cascades. Increasing the threshold to |log2 fold change|>1 and p < 0.01 revealed 48 differentially expressed miRNAs, 31 of which were novel miRNAs. Thirteen of these novel miRNAs, which were differentially expressed for at least two time points, were detected via RT-qPCR assays. The novel_229, novel_609, novel_973 and oar-miR-181a assessed by RT-qPCR were detectable and consistent with the expression patterns obtained by miRNA sequencing. Functional analyses of these miRNAs demonstrated that their target genes participated in the immune response pathways, including the innate and adaptive immunity pathways. The immune-related target genes of novel_229 included ENSOARG00000000649 and TMED1, as well as LCN2, PDPK1 and LPO were novel_609 target genes. The immune-related target genes of novel_973 included C6orf58, SPPL3, BPIFB1, ENSOARG00000021083, MPTX1, CCL28, FGB, IDO1, OLR1 and ENSOARG00000020393. The immune-related target genes of oar-miR-181a included ENSOARG00000002722, ARHGEF2, MFAP4 and DOK2. These results will deepen our understanding of the host miRNA-driven defense mechanism in sheep immunized with B.suis S2 vaccine, and provide the valuable information for optimizing vaccines and developing molecular diagnostic targets.

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“…Controlling TCR signaling by miR-181a is also important for the development of regulatory T cells and several innate-like T cell populations, including invariant natural killer T (iNKT) cells and mucosal associated invariant T (MAIT) cells, that are also generated from double-positive thymocytes [ 35 , 36 ]. In contrast, miR-181a does not appear to control the generation of γδ T cells which develop from DN thymocytes [ 37 ].…”

Section: Mir-181a and T Cell Developmentmentioning

confidence: 99%

miR-181a-regulated pathways in T-cell differentiation and aging

Kim

Weyand

et al. 2021

Immun Ageing

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MicroRNAs (miRNAs) are regulatory noncoding RNAs important for many aspects of cellular processes including cell differentiation and proliferation. Functions of numerous miRNAs have been identified in T cells, with miR-181a regulating T cell activation thresholds during thymic T cell development and during activation of peripheral T cells. Intriguingly, miR-181a is implicated in defective antiviral and vaccine responses in older individuals, as its expression declines in naïve T cells with increasing age. Here, we review the pathways that are regulated by miR-181a and that explain the unique role of miR-181a in T cell development, T cell activation and antiviral T cell responses. These studies provide a framework for understanding how a decline in miR-181a expression in T cells could contribute to age-related defects in adaptive immunity. We furthermore review the mechanisms that cause the age-related decline in miR-181a expression and discuss the potential of restoring miR-181a expression or targeting miR-181a-regulated pathways to improve impaired T cell responses in older individuals.

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MicroRNA miR-181—A Rheostat for TCR Signaling in Thymic Selection and Peripheral T-Cell Function

Cited by 19 publications

References 94 publications

Noncanonical Function of AGO2 Augments T-cell Receptor Signaling in T-cell Prolymphocytic Leukemia

Noncanonical Function of AGO2 Augments T-cell Receptor Signaling in T-cell Prolymphocytic Leukemia

Downregulation of Three Novel miRNAs in the Lymph Nodes of Sheep Immunized With the Brucella suis Strain 2 Vaccine

miR-181a-regulated pathways in T-cell differentiation and aging

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