Transcriptomic effects of rs4845604, an IBD and allergy-associated RORC variant, in stimulated ex vivo CD4+ T cells

RORγt is an isoform of RORC, preferentially expressed in Th17 cells, that functions as a critical regulator of type 3 immunity. As murine Th17-driven inflammatory disease models were greatly diminished in RORC knock-out mice, this receptor was prioritised as an attractive therapeutic target for the...

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Autores principales:	Paul A. Wilson, Sara Santos Franco, Liu He, Nicholas W. Galwey, Jackie Meakin, Rebecca McIntyre, Simon M. McHugh, Michael A. Nolan, Sarah L. Spain, Thaddeus Carlson, Mercedes Lobera, Justin P. Rubio, Bill Davis, Linda C. McCarthy
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/379c1f72bac84bec9638d701c7a4dcef
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spelling	oai:doaj.org-article:379c1f72bac84bec9638d701c7a4dcef2021-11-04T06:07:16ZTranscriptomic effects of rs4845604, an IBD and allergy-associated RORC variant, in stimulated ex vivo CD4+ T cells1932-6203https://doaj.org/article/379c1f72bac84bec9638d701c7a4dcef2021-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530322/?tool=EBIhttps://doaj.org/toc/1932-6203RORγt is an isoform of RORC, preferentially expressed in Th17 cells, that functions as a critical regulator of type 3 immunity. As murine Th17-driven inflammatory disease models were greatly diminished in RORC knock-out mice, this receptor was prioritised as an attractive therapeutic target for the treatment of several autoimmune diseases. Human genetic studies indicate a significant contributory role for RORC in several human disease conditions. Furthermore, genome-wide association studies (GWAS) report a significant association between inflammatory bowel disease (IBD) and the RORC regulatory variant rs4845604. To investigate if the rs4845604 variant may affect CD4+ T cell differentiation events, naïve CD4+ T cells were isolated from eighteen healthy subjects homozygous for the rs4845604 minor (A) or major (G) allele). Isolated cells from each subject were differentiated into distinct T cell lineages by culturing in either T cell maintenance medium or Th17 driving medium conditions for six days in the presence of an RORC inverse agonist (to prevent constitutive receptor activity) or an inactive diastereomer (control). Our proof of concept study indicated that genotype had no significant effect on the mean number of naïve CD4 T cells isolated, nor the frequency of Th1-like and Th17-like cells following six days of culture in any of the four culture conditions. Analysis of the derived RNA-seq count data identified genotype-driven transcriptional effects in each of the four culture conditions. Subsequent pathway enrichment analysis of these profiles reported perturbation of metabolic signalling networks, with the potential to affect the cellular detoxification response. This investigation reveals that rs4845604 genotype is associated with transcriptional effects in CD4+ T cells that may perturb immune and metabolic pathways. Most significantly, the rs4845604 GG, IBD risk associated, genotype may be associated with a differential detoxification response. This observation justifies further investigation in a larger cohort of both healthy and IBD-affected individuals.Paul A. WilsonSara Santos FrancoLiu HeNicholas W. GalweyJackie MeakinRebecca McIntyreSimon M. McHughMichael A. NolanSarah L. SpainThaddeus CarlsonMercedes LoberaJustin P. RubioBill DavisLinda C. McCarthyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Paul A. Wilson Sara Santos Franco Liu He Nicholas W. Galwey Jackie Meakin Rebecca McIntyre Simon M. McHugh Michael A. Nolan Sarah L. Spain Thaddeus Carlson Mercedes Lobera Justin P. Rubio Bill Davis Linda C. McCarthy Transcriptomic effects of rs4845604, an IBD and allergy-associated RORC variant, in stimulated ex vivo CD4+ T cells
description	RORγt is an isoform of RORC, preferentially expressed in Th17 cells, that functions as a critical regulator of type 3 immunity. As murine Th17-driven inflammatory disease models were greatly diminished in RORC knock-out mice, this receptor was prioritised as an attractive therapeutic target for the treatment of several autoimmune diseases. Human genetic studies indicate a significant contributory role for RORC in several human disease conditions. Furthermore, genome-wide association studies (GWAS) report a significant association between inflammatory bowel disease (IBD) and the RORC regulatory variant rs4845604. To investigate if the rs4845604 variant may affect CD4+ T cell differentiation events, naïve CD4+ T cells were isolated from eighteen healthy subjects homozygous for the rs4845604 minor (A) or major (G) allele). Isolated cells from each subject were differentiated into distinct T cell lineages by culturing in either T cell maintenance medium or Th17 driving medium conditions for six days in the presence of an RORC inverse agonist (to prevent constitutive receptor activity) or an inactive diastereomer (control). Our proof of concept study indicated that genotype had no significant effect on the mean number of naïve CD4 T cells isolated, nor the frequency of Th1-like and Th17-like cells following six days of culture in any of the four culture conditions. Analysis of the derived RNA-seq count data identified genotype-driven transcriptional effects in each of the four culture conditions. Subsequent pathway enrichment analysis of these profiles reported perturbation of metabolic signalling networks, with the potential to affect the cellular detoxification response. This investigation reveals that rs4845604 genotype is associated with transcriptional effects in CD4+ T cells that may perturb immune and metabolic pathways. Most significantly, the rs4845604 GG, IBD risk associated, genotype may be associated with a differential detoxification response. This observation justifies further investigation in a larger cohort of both healthy and IBD-affected individuals.
format	article
author	Paul A. Wilson Sara Santos Franco Liu He Nicholas W. Galwey Jackie Meakin Rebecca McIntyre Simon M. McHugh Michael A. Nolan Sarah L. Spain Thaddeus Carlson Mercedes Lobera Justin P. Rubio Bill Davis Linda C. McCarthy
author_facet	Paul A. Wilson Sara Santos Franco Liu He Nicholas W. Galwey Jackie Meakin Rebecca McIntyre Simon M. McHugh Michael A. Nolan Sarah L. Spain Thaddeus Carlson Mercedes Lobera Justin P. Rubio Bill Davis Linda C. McCarthy
author_sort	Paul A. Wilson
title	Transcriptomic effects of rs4845604, an IBD and allergy-associated RORC variant, in stimulated ex vivo CD4+ T cells
title_short	Transcriptomic effects of rs4845604, an IBD and allergy-associated RORC variant, in stimulated ex vivo CD4+ T cells
title_full	Transcriptomic effects of rs4845604, an IBD and allergy-associated RORC variant, in stimulated ex vivo CD4+ T cells
title_fullStr	Transcriptomic effects of rs4845604, an IBD and allergy-associated RORC variant, in stimulated ex vivo CD4+ T cells
title_full_unstemmed	Transcriptomic effects of rs4845604, an IBD and allergy-associated RORC variant, in stimulated ex vivo CD4+ T cells
title_sort	transcriptomic effects of rs4845604, an ibd and allergy-associated rorc variant, in stimulated ex vivo cd4+ t cells
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/379c1f72bac84bec9638d701c7a4dcef
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Transcriptomic effects of rs4845604, an IBD and allergy-associated RORC variant, in stimulated ex vivo CD4+ T cells

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