MicroRNAs of the miR-17∼92 family are critical regulators of TFH differentiation

Kang, Seung Goo; Liu, Wen‐Hsien; Lu, Peiwen; Jin, Hyun Yong; Lim, Hyung W.; Shepherd, Jovan; Fremgen, Daniel; Verdin, Eric; Oldstone, Michael B. A.; Qi, Hai; Teijaro, John R.; Xiao, Changchun

doi:10.1038/ni.2648

Cited by 163 publications

(196 citation statements)

References 39 publications

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“…Mice with Tcellspecific loss of miR1792 cluster exhibit severely compromised Tfh cell differentiation, germinal center formation, and antibody responses. On the contrary, Tcellspecific miR1792 cluster transgenic mice spontaneously accumulate Tfh cells [99] . miR10a attenuates phenotypic conversion of iTreg cells to Tfh cells by simultaneously targeting Bcl6, a transcription factor critical for Tfh cell differentiation [101] , along with the corepressor Ncor2 [90] .…”

Section: Mirnas and Follicular Helper T Cellsmentioning

confidence: 99%

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miRNAs as new molecular insights into inflammatory bowel disease: Crucial regulators in autoimmunity and inflammation

Zhang

2016

WJG

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Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammatory disorders of the gastrointestinal tract, and includes two major phenotypes: ulcerative colitis and Crohn's disease. The pathogenesis of IBD is not fully understood as of yet. It is believed that IBD results from complicated interactions between environmental factors, genetic predisposition, and immune disorders. miRNAs are a class of small non-coding RNAs that can regulate gene expression by targeting the 3′-untranslated region of specific mRNAs for degradation or translational inhibition. miRNAs are considered to play crucial regulatory roles in many biologic processes, such as immune cellular differentiation, proliferation, and apoptosis, and maintenance of immune homeostasis. Recently, aberrant expression of miRNAs was revealed to play an important role in autoimmune diseases, including IBD. In this review, we discuss the current understanding of how miRNAs regulate autoimmunity and inflammation by affecting the differentiation, maturation, and function of various immune cells. In particular, we focus on describing specific miRNA expression profiles in tissues and peripheral blood that may be associated with the pathogenesis of IBD. In addition, we summarize the opportunities for utilizing miRNAs as new biomarkers and as potential therapeutic targets in IBD.

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Section: Mirnas and Follicular Helper T Cellsmentioning

confidence: 99%

“…Several studies have demonstrated that miRNAs are crucial for Tfh cell differentiation and function [99,100] . Mice with Tcellspecific loss of miR1792 cluster exhibit severely compromised Tfh cell differentiation, germinal center formation, and antibody responses.…”

Section: Mirnas and Follicular Helper T Cellsmentioning

confidence: 99%

miRNAs as new molecular insights into inflammatory bowel disease: Crucial regulators in autoimmunity and inflammation

Zhang

2016

WJG

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“…These include lymphoid enhancer‐binding factor 1 (LEF‐1) and T‐cell‐specific transcription factor 1 (TCF‐1), which act upstream of Bcl6 to promote Tfh cell differentiation140, 141, 142; basic leucine zipper transcription factor ATF‐like (Batf), which positively regulates Bcl6 and is important for IL‐4 expression143; interferon regulatory factor 4 (IRF4), which drives differentiation of IL‐12‐stimulated CD4 T cells to Tfh rather than Th1 cells144; achaete‐scute homolog 2 (Ascl2), which induces CXCR5 expression145; c‐Maf, which enhances expression of CXCR5, IL‐21, and IL‐4146; signal transducer and activator of transcription (STAT)s, STAT3 and 4 being particularly important for human Tfh cell differentiation and regulation of IL‐21 expression by human CD4 + T cells121, 147; and forkhead box protein O1 (FOXO1), which can both promote and inhibit Tfh cell differentiation 148. In addition, Tfh cell differentiation is regulated by microRNAs including members of the miRNA‐17‐92 family 149, 150. Bcl6 is a transcriptional repressor and orchestrates the expression of genes involved in Tfh cell migration, differentiation, and function as well as repressing genes involved in alternative fate differentiation 151.…”

Section: T Follicular Helper Cells and Their Role In Bnab Inductionmentioning

confidence: 99%

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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SummaryInduction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV‐1) is a key, as‐yet‐unachieved goal of prophylactic HIV‐1 vaccine strategies. However, some HIV‐infected individuals develop bnAbs after approximately 2‐4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4+ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4+ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy‐chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4+ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV‐1 infection, in particular alterations in CD4+ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV‐1 vaccine design.

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“…microRNAs regulate gene expression at the posttranscriptional level through mRNA stability and translation (Selbach et al, 2008). microRNAs control multiple aspects of T cell differentiation and activation, from initial signaling events (Li et al, 2007) to the acquisition of effector functions and cytokine production (Muljo et al, 2005;Steiner et al, 2011), the resolution of T cell responses (Zhang and Bevan, 2010;Yang et al, 2012) and the choice of T cell fates including T helper cell lineage (Muljo et al, 2005;Steiner et al, 2011;Baumjohann et al, 2013;Kang et al, 2013;Khan et al, 2013), the formation of memory cells (Khan et al, 2013), and regulatory T cell differentiation (Cobb et al, 2006;Liston et al, 2008;Zhou et al, 2008;Lu et al, 2010).…”

Section: Dicer-deficient Cd4 T Cells Show Heightened Sensitivity To Tmentioning

confidence: 99%

microRNA-mediated regulation of mTOR complex components facilitates discrimination between activation and anergy in CD4 T cells

Marçais¹,

Blevins²,

Graumann³

et al. 2014

J Cell Biol

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T cell receptor (TCR) signals can elicit full activation with acquisition of effector functions or a state of anergy. Here, we ask whether microRNAs affect the interpretation of TCR signaling. We find that Dicer-deficient CD4 T cells fail to correctly discriminate between activating and anergy-inducing stimuli and produce IL-2 in the absence of co-stimulation. Excess IL-2 production by Dicer-deficient CD4 T cells was sufficient to override anergy induction in WT T cells and to restore inducible Foxp3 expression in Il2-deficient CD4 T cells. Phosphorylation of Akt on S473 and of S6 ribosomal protein was increased and sustained in Dicer-deficient CD4 T cells, indicating elevated mTOR activity. The mTOR components Mtor and Rictor were posttranscriptionally deregulated, and the microRNAs Let-7 and miR-16 targeted the Mtor and Rictor mRNAs. Remarkably, returning Mtor and Rictor to normal levels by deleting one allele of Mtor and one allele of Rictor was sufficient to reduce Akt S473 phosphorylation and to reduce co-stimulation-independent IL-2 production in Dicer-deficient CD4 T cells. These results show that microRNAs regulate the expression of mTOR components in T cells, and that this regulation is critical for the modulation of mTOR activity. Hence, microRNAs contribute to the discrimination between T cell activation and anergy.

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MicroRNAs of the miR-17∼92 family are critical regulators of TFH differentiation

Cited by 163 publications

References 39 publications

miRNAs as new molecular insights into inflammatory bowel disease: Crucial regulators in autoimmunity and inflammation

miRNAs as new molecular insights into inflammatory bowel disease: Crucial regulators in autoimmunity and inflammation

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

microRNA-mediated regulation of mTOR complex components facilitates discrimination between activation and anergy in CD4 T cells

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