Mapping Rora Expression in Resting and Activated CD4+ T Cells

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2021 May 18

PMID 34003838

Citations 18

Authors

Liora Haim-Vilmovsky

Johan Henriksson

Jennifer A Walker

Zhichao Miao

Eviatar Natan

Gozde Kar

Simon Clare

Jillian L Barlow

Evelina Charidemou

Lira Mamanova

Xi Chen

Valentina Proserpio

Jhuma Pramanik

Steven Woodhouse

Anna V Protasio

Mirjana Efremova

Julian L Griffin

Matt Berriman

Gordon Dougan

Jasmin Fisher

John C Marioni

Andrew N J McKenzie

Sarah A Teichmann

Affiliations

Soon will be listed here.

Abstract

The transcription factor Rora has been shown to be important for the development of ILC2 and the regulation of ILC3, macrophages and Treg cells. Here we investigate the role of Rora across CD4+ T cells in general, but with an emphasis on Th2 cells, both in vitro as well as in the context of several in vivo type 2 infection models. We dissect the function of Rora using overexpression and a CD4-conditional Rora-knockout mouse, as well as a RORA-reporter mouse. We establish the importance of Rora in CD4+ T cells for controlling lung inflammation induced by Nippostrongylus brasiliensis infection, and have measured the effect on downstream genes using RNA-seq. Using a systematic stimulation screen of CD4+ T cells, coupled with RNA-seq, we identify upstream regulators of Rora, most importantly IL-33 and CCL7. Our data suggest that Rora is a negative regulator of the immune system, possibly through several downstream pathways, and is under control of the local microenvironment.

Citing Articles

Genetic determinants of skin ageing: a systematic review and meta-analysis of genome-wide association studies and candidate genes.

Wong C, Ng J, Sio Y, Chew F J Physiol Anthropol. 2025; 44(1):4.

PMID: 39923055 PMC: 11806588. DOI: 10.1186/s40101-025-00384-9.

Rani A Front Endocrinol (Lausanne). 2024; 14:1300729.

PMID: 38766309 PMC: 11099308. DOI: 10.3389/fendo.2023.1300729.

Deciphering the developmental trajectory of tissue-resident Foxp3 regulatory T cells.

Alvarez F, Liu Z, Bay A, Piccirillo C Front Immunol. 2024; 15:1331846.

PMID: 38605970 PMC: 11007185. DOI: 10.3389/fimmu.2024.1331846.

Targeting pro-inflammatory T cells as a novel therapeutic approach to potentially resolve atherosclerosis in humans.

Fan L, Liu J, Hu W, Chen Z, Lan J, Zhang T Cell Res. 2024; 34(6):407-427.

PMID: 38491170 PMC: 11143203. DOI: 10.1038/s41422-024-00945-0.

Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy.

Racine J, Bachman J, Zhang J, Misherghi A, Khadour R, Kaisar S J Immunol. 2024; 212(8):1287-1306.

PMID: 38426910 PMC: 10984778. DOI: 10.4049/jimmunol.2300841.

References

Jetten A, Kang H, Takeda Y . Retinoic acid-related orphan receptors α and γ: key regulators of lipid/glucose metabolism, inflammation, and insulin sensitivity. Front Endocrinol (Lausanne). 2013; 4:1. PMC: 3555121. DOI: 10.3389/fendo.2013.00001. View

Khaled A, Durum S . Lymphocide: cytokines and the control of lymphoid homeostasis. Nat Rev Immunol. 2002; 2(11):817-30. DOI: 10.1038/nri931. View

Gasteiger G, Fan X, Dikiy S, Lee S, Rudensky A . Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science. 2015; 350(6263):981-5. PMC: 4720139. DOI: 10.1126/science.aac9593. View

He W, Holtkamp S, Hergenhan S, Kraus K, de Juan A, Weber J . Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues. Immunity. 2018; 49(6):1175-1190.e7. PMC: 6303219. DOI: 10.1016/j.immuni.2018.10.007. View

Kim K, Boo K, Yu Y, Oh S, Kim H, Jeon Y . RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network. Nat Commun. 2017; 8(1):162. PMC: 5534431. DOI: 10.1038/s41467-017-00215-1. View

Vulcano M, Albanesi C, Stoppacciaro A, Bagnati R, DAmico G, Struyf S . Dendritic cells as a major source of macrophage-derived chemokine/CCL22 in vitro and in vivo. Eur J Immunol. 2001; 31(3):812-22. DOI: 10.1002/1521-4141(200103)31:3<812::aid-immu812>3.0.co;2-l. View

McCarthy D, Campbell K, Lun A, Wills Q . Scater: pre-processing, quality control, normalization and visualization of single-cell RNA-seq data in R. Bioinformatics. 2017; 33(8):1179-1186. PMC: 5408845. DOI: 10.1093/bioinformatics/btw777. View

Stubbington M, Mahata B, Svensson V, Deonarine A, Nissen J, Betz A . An atlas of mouse CD4(+) T cell transcriptomes. Biol Direct. 2015; 10:14. PMC: 4384382. DOI: 10.1186/s13062-015-0045-x. View

Pau G, Fuchs F, Sklyar O, Boutros M, Huber W . EBImage--an R package for image processing with applications to cellular phenotypes. Bioinformatics. 2010; 26(7):979-81. PMC: 2844988. DOI: 10.1093/bioinformatics/btq046. View

10.

Patro R, Duggal G, Love M, Irizarry R, Kingsford C . Salmon provides fast and bias-aware quantification of transcript expression. Nat Methods. 2017; 14(4):417-419. PMC: 5600148. DOI: 10.1038/nmeth.4197. View

11.

Picelli S, Faridani O, Bjorklund A, Winberg G, Sagasser S, Sandberg R . Full-length RNA-seq from single cells using Smart-seq2. Nat Protoc. 2014; 9(1):171-81. DOI: 10.1038/nprot.2014.006. View

12.

Halim T, MacLaren A, Romanish M, Gold M, McNagny K, Takei F . Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation. Immunity. 2012; 37(3):463-74. DOI: 10.1016/j.immuni.2012.06.012. View

13.

Jung D, Kim J, Kim C, Song S . Embigin is overexpressed in pancreatic ductal adenocarcinoma and regulates cell motility through epithelial to mesenchymal transition via the TGF-β pathway. Mol Carcinog. 2015; 55(5):633-45. DOI: 10.1002/mc.22309. View

14.

Moon J, Chu H, Pepper M, McSorley S, Jameson S, Kedl R . Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity. 2007; 27(2):203-13. PMC: 2200089. DOI: 10.1016/j.immuni.2007.07.007. View

15.

Stubbington M, Lonnberg T, Proserpio V, Clare S, Speak A, Dougan G . T cell fate and clonality inference from single-cell transcriptomes. Nat Methods. 2016; 13(4):329-332. PMC: 4835021. DOI: 10.1038/nmeth.3800. View

16.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

17.

Bray N, Pimentel H, Melsted P, Pachter L . Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol. 2016; 34(5):525-7. DOI: 10.1038/nbt.3519. View

18.

Fei F, Qu J, Zhang M, Li Y, Zhang S . S100A4 in cancer progression and metastasis: A systematic review. Oncotarget. 2017; 8(42):73219-73239. PMC: 5641208. DOI: 10.18632/oncotarget.18016. View

19.

Li M, Ransohoff R . Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology. Prog Neurobiol. 2008; 84(2):116-31. PMC: 2324067. DOI: 10.1016/j.pneurobio.2007.11.003. View

20.

Pulendran B, Artis D . New paradigms in type 2 immunity. Science. 2012; 337(6093):431-5. PMC: 4078898. DOI: 10.1126/science.1221064. View