Transcriptomics identified a critical role for Th2 cell-intrinsic miR-155 in mediating allergy and antihelminth immunity

Okoye, Isobel; Czieso, Stephanie; Ktistaki, Eleni; Roderick, Kathleen; Coomes, Stephanie M.; Pelly, Victoria S.; Kannan, Yashaswini; Perez-Lloret, Jimena; Zhao, Jimmy L.; Baltimore, David; Langhorne, Jean; Wilson, Mark S.

doi:10.1073/pnas.1406322111

Cited by 120 publications

(130 citation statements)

References 75 publications

Supporting

Mentioning

119

Contrasting

Unclassified

Order By: Relevance

“…A separate report in human T-cell subsets also identified Blimp-1 and IFN-γ mRNAs as being targets of miR-125b, a signature miRNA of naïve CD4 + T cells responsible to block their differentiation into effector cells [9]. In sum, multiple miRNAs control IFN-γ and type 1 differentiation pathway (Table 1) Conflicting results were observed in an independent study by Wilson and colleagues, which used several in vivo models of Th2 response [67]. In this study miR-155 was essential to mount a protective Th2 response against house dust mites and helminths and lower levels of miR-155 in T cells led to a reduction in IL-13 production and reduced inflammation [67].…”

mentioning

confidence: 97%

Cross‐regulation between cytokine and microRNA pathways in T cells

et al. 2015

View full text Add to dashboard Cite

microRNA (miRNA) mediated regulation of protein expression has emerged as an important mechanism in T-cell physiology, from development and survival to activation, proliferation, and differentiation. One of the major classes of proteins involved in these processes are cytokines, which are both key input signals and major products of T-cell function. Here, we summarize the current data on the molecular cross-talk between cytokines and miRNAs: how cytokines regulate miRNA expression, and how specific miRNAs control cytokine production in T cells. We also describe the inflammatory consequences of deregulating the miRNA/cytokine axis in mice and humans. We believe this topical area will have key implications for immune modulation and treatment of autoimmune pathology. Keywords:Cytokines r Inflammation r miRNA r T cells microRNAs as regulators of protein expressionBiological processes require the integration of environmental stimuli at the level of gene expression. The robustness of genetic networks depends on the distinction between physiological responses (to particular cues) and biological "noise" (stochastic variations), which can be achieved, for example, by establishing feed-forward transcriptional loops. Over the past two decades, a new mechanism that interacts with transcriptional loops and sets additional thresholds, which enable cells to filter physiological signals from noise has emerged; this mechanism regulates gene expression at the posttranscriptional level and relies on microRNAs (miRNAs; reviewed in [1]). These are an abundant class of evolutionarily conserved small noncoding (untranslated) RNA species that control target mRNA stability, degradation, and translation, thus affecting the majority of mammalian genes [2].Correspondence: Dr. Anita Q. Gomes e-mail: anitagomes@medicina.ulisboa.ptIn the conventional miRNA biogenesis pathway, RNA polymerase II transcribed pri-miRNAs are processed by the nuclear RNase III enzyme Drosha (complexed with DGCR8) to generate 60-70 nt stem-loop intermediates, the pre-miRNAs, that are further processed into 19-24mers in the cytoplasm by another key RNase III, Dicer. Mature miRNAs are then incorporated into RNAinduced silencing complexes, whose core components are proteins of the Argonaute family (Ago1-4), which use the 5 end (nucleotides 2-8) "seed sequence" of the miRNA to recognize complementary mRNA transcripts (mostly in their 3 untranslated region) for deadenylation or inhibition of translation, ultimately resulting in mRNA decapping and decay (reviewed in [3,4]).Unique spatial and temporal expression patterns in distinct hematopoietic cell lineages are suggestive of multiple roles for miRNAs in hematopoiesis, self-tolerance, and in immune responses, which have been explored over the past decade (reviewed in [5,6]). Over a 100 different miRNAs have been shown to be expressed by cells of the immune system, where * These authors contributed equally to this work as first authors. * * These authors contributed equally to this work as last authors.C 2015 WILEY-VCH Ve...

show abstract

mentioning

confidence: 97%

Cross‐regulation between cytokine and microRNA pathways in T cells

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Dysregulated T H 2-cell responses following allergen exposure contribute directly to allergic disease (32). We recently reported that HDM-or helminthelicited T H 2 cells have distinct transcriptional profiles, compared with ex vivo T H 1, T H 17, and natural Treg cells (33). Using these transcriptional datasets (more than twofold change relative to naive T cells, P < 0.05) we applied in silico upstream regulator analyses (Ingenuity Pathways Analysis, IPA) (34) and generated a z-score representing the likelihood of activity of putative transcriptional regulators.…”

Section: Resultsmentioning

confidence: 99%

“…Cytokine and chemokine-secreting T H 2 cells orchestrate many of the pathophysiological features of allergic asthma. We therefore interrogated the transcriptional profile of highly purified T H 2 cells that contribute directly to HDM-induced airway allergy, in addition to T H 2 cells isolated from helminth-infected mice (33). Rather than focusing on differentially regulated genes in the datasets, we focused on putative upstream pathways that could contribute to the transcriptional profiles.…”

Section: Discussionmentioning

confidence: 99%

“…There are many miRNAs that are predicted to target Trim24, which, if down-regulated in T H 2 cells, could permit the translation of Trim24 without altering the transcription of Trim24. For example, miR-384 and miR-539 are predicted to target Trim24 and are down-regulated in T H 2 cells (33). Whether these or other miRNA-mediated pathways regulate Trim24 expression in T cells requires further validation.…”

Section: Discussionmentioning

confidence: 99%

“…Although a variety of immune cells contribute to allergy, cytokine-secreting αβ + CD4 + T-helper 2 (T H 2) cells orchestrate the type-2-driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic T H 2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic T H cells [Okoye IS, et al (2014) Proc Natl Acad Sci USA 111(30):E3081-E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)-and helminth-elicited Il4 gfp+ αβ + CD4 + T H 2 cells but not in T H 1, T H 17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell-intrinsic Trim24 is essential for HDMmediated airway allergy and antihelminth immunity.…”

mentioning

confidence: 99%

See 2 more Smart Citations

T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on T_H2 cells and T_H2 cell-mediated airway allergy

Perez-Lloret

Okoye

Guidi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αβ+CD4+ T-helper 2 (TH2) cells orchestrate the type-2–driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081–E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4gfp+αβ+CD4+ TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell–intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24−/− T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1–regulated signaling. Following this prediction, we found that Trim24−/− T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1β–mediated activation in vitro and in vivo, and fail to respond to IL-1β–exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell–intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity.

show abstract

Adaptive Immunity and Metabolic Health: Harmony Becomes Dissonant in Obesity and Aging

Bharath

Nikolajczyk³

2017

Comprehensive Physiology

View full text Add to dashboard Cite

Adipose tissue (AT) is the primary energy reservoir organ, and thereby plays a critical role in energy homeostasis and regulation of metabolism. AT expands in response to chronic overnutrition or aging and becomes a major source of inflammation that has marked influence on systemic metabolism. The chronic, sterile inflammation that occurs in the AT during the development of obesity or in aging contributes to onset of devastating diseases such as insulin resistance, diabetes, and cardiovascular pathologies. Numerous studies have shown that inflammation in the visceral AT of humans and animals is a critical trigger for the development of metabolic syndrome. This work underscores the well-supported conclusion that the inflammatory immune response and metabolic pathways in the AT are tightly interwoven by multiple layers of relatively conserved mechanisms. During the development of diet-induced obesity or age-associated adiposity, cells of the innate and the adaptive immune systems infiltrate and proliferate in the AT. Macrophages, which dominate AT-associated immune cells in mouse models of obesity, but are less dominant in obese people, have been studied extensively. However, cells of the adaptive immune system, including T cells and B cells, contribute significantly to AT inflammation, perhaps more in humans than in mice. Lymphocytes regulate recruitment of innate immune cells into AT, and produce cytokines that influence the helpful-to-harmful inflammatory balance that, in turn, regulates organismal metabolism. This review describes inflammation, or more precisely, metabolic inflammation (metaflammation) with an eye toward the AT and the roles lymphocytes play in regulation of systemic metabolism during obesity and aging. © 2017 American Physiological Society. Compr Physiol 7:1307-1337, 2017.

show abstract

Transcriptomics identified a critical role for Th2 cell-intrinsic miR-155 in mediating allergy and antihelminth immunity

Cited by 120 publications

References 75 publications

Cross‐regulation between cytokine and microRNA pathways in T cells

Cross‐regulation between cytokine and microRNA pathways in T cells

T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on T_H2 cells and T_H2 cell-mediated airway allergy

Adaptive Immunity and Metabolic Health: Harmony Becomes Dissonant in Obesity and Aging

Contact Info

Product

Resources

About

Transcriptomics identified a critical role for Th2 cell-intrinsic miR-155 in mediating allergy and antihelminth immunity

Cited by 120 publications

References 75 publications

Cross‐regulation between cytokine and microRNA pathways in T cells

Cross‐regulation between cytokine and microRNA pathways in T cells

T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy

Adaptive Immunity and Metabolic Health: Harmony Becomes Dissonant in Obesity and Aging

Contact Info

Product

Resources

About

T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on T_H2 cells and T_H2 cell-mediated airway allergy