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

Okoye, Isobel S. and Czieso, Stephanie and Ktistaki, Eleni and Roderick, Kathleen and Coomes, Stephanie M. and Pelly, Victoria S. and Kannan, Yashaswini and Lloret-Perez, Jimena and Zhao, Jimmy L. and Baltimore, David and Langhorne, Jean and Wilson, Mark S. (2014) Transcriptomics identified a critical role for Th2 cell-intrinsic miR-155 in mediating allergy and antihelminth immunity. Proceedings of the National Academy of Sciences of the United States of America, 111 (30). E3081-E3090. ISSN 0027-8424. PMCID PMC4121777. https://resolver.caltech.edu/CaltechAUTHORS:20140721-090655047

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Abstract

Allergic diseases, orchestrated by hyperactive CD4^(+) Th2 cells, are some of the most common global chronic diseases. Therapeutic intervention relies upon broad-scale corticosteroids with indiscriminate impact. To identify targets in pathogenic Th2 cells, we took a comprehensive approach to identify the microRNA (miRNA) and mRNA transcriptome of highly purified cytokine-expressing Th1, Th2, Th9, Th17, and Treg cells both generated in vitro and isolated ex vivo from allergy, infection, and autoimmune disease models. We report here that distinct regulatory miRNA networks operate to regulate Th2 cells in house dust mite-allergic or helminth-infected animals and in vitro Th2 cells, which are distinguishable from other T cells. We validated several miRNA (miR) candidates (miR-15a, miR-20b, miR-146a, miR-155, and miR-200c), which targeted a suite of dynamically regulated genes in Th2 cells. Through in-depth studies using miR-155^(−/−) or miR-146a^(−/−) T cells, we identified that T-cell–intrinsic miR-155 was required for type-2 immunity, in part through regulation of S1pr1, whereas T-cell–intrinsic miR-146a was required to prevent overt Th1/Th17 skewing. These data identify miR-155, but not miR-146a, as a potential therapeutic target to alleviate Th2-medited inflammation and allergy.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1406322111DOIArticle
http://www.pnas.org/cgi/doi/10.1073/pnas.1406322111PublisherArticle
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1406322111/-/DCSupplementalPublisherSupporting Information
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121777/PubMed CentralArticle
ORCID:
AuthorORCID
Baltimore, David0000-0001-8723-8190
Additional Information:© 2014 National Academy of Sciences. Early edition. Edited by Robert L. Coffman, Dynavax Technologies, Berkeley, CA, and approved June 23, 2014 (received for review April 8, 2014). We thank Abdul Sesay, Harsha Jani, and Leena Bhaw-Rosun [Systems Biology Department, National Institute for Medical Research (NIMR)] for help with microarray experiments; Radma Mahmood and Radika Anand for help with histology; Samir Kelada (University of North Carolina at Chapel Hill) for help with transcriptional analysis; Natalia Dinischitou (Immune Cell Biology, NIMR), for help with expanding and purifying plasmids; Brigitta Stockinger and Alexandre Potocnik for Il17a^(Cre), Il9^(Cre), R26^(eFP635) mice; Joao Duarte for help with experimental autoimmune encephalomyelitis experiments; Graham Preece, Wayne Turnbull, and Bhavik Patel for assistance with flow cytometry-related sorting and analysis; and Trisha Norton, Keith Williams, Adebambo Adekoya, and the B2 and Building C staff for animal husbandry. This work was supported by the Medical Research Council (file reference nos. MC_UP_A253_1028 and U117584248). Author contributions: I.S.O. and M.S.W. designed research; I.S.O., S.C., E.K., K.R., S.M.C., V.S.P., Y.K., J.P.-L., and M.S.W. performed research; J.L.Z., D.B., and J.L. contributed new reagents/analytic tools; I.S.O., S.M.C., V.S.P., Y.K., J.L.Z., D.B., J.L., and M.S.W. analyzed data; and I.S.O. and M.S.W. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1406322111/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
Medical Research Council (UK)MC_UP_A253_1028
Medical Research Council (UK)U117584248
Issue or Number:30
PubMed Central ID:PMC4121777
Record Number:CaltechAUTHORS:20140721-090655047
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140721-090655047
Official Citation:Isobel S. Okoye, Stephanie Czieso, Eleni Ktistaki, Kathleen Roderick, Stephanie M. Coomes, Victoria S. Pelly, Yashaswini Kannan, Jimena Perez-Lloret, Jimmy L. Zhao, David Baltimore, Jean Langhorne, and Mark S. Wilson Transcriptomics identified a critical role for Th2 cell-intrinsic miR-155 in mediating allergy and antihelminth immunity PNAS 2014 111 (30) E3081-E3090; published ahead of print July 14, 2014, doi:10.1073/pnas.1406322111
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:47356
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:22 Jul 2014 15:48
Last Modified:03 Oct 2019 06:52

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