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Original article
Generation of primary human intestinal T cell transcriptomes reveals differential expression at genetic risk loci for immune-mediated disease
  1. Tim Raine1,
  2. Jimmy Z Liu2,
  3. Carl A Anderson2,
  4. Miles Parkes1,
  5. Arthur Kaser1
  1. 1Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
  2. 2Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
  1. Correspondence to Dr Tim Raine, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ UK; tr223{at}cam.ac.uk

Abstract

Objective Genome-wide association studies (GWAS) have identified genetic variants within multiple risk loci as predisposing to intestinal inflammatory diseases, including Crohn's disease, ulcerative colitis and coeliac disease. Most risk variants affect regulation of transcription, but a critical challenge is to identify which genes and which cell types these variants affect. We aimed to characterise whole transcriptomes for each common T lymphocyte subset resident within the gut mucosa, and use these to infer biological insights and highlight candidate genes of interest within GWAS risk loci.

Design We isolated the four major intestinal T cell populations from pinch biopsies from healthy subjects and generated transcriptomes for each. We computationally integrated these transcriptomes with GWAS data from immune-related diseases.

Results Robust, high quality transcriptomic data were generated from 1 ng of RNA from precisely sorted cell subsets. Gene expression patterns clearly differentiated intestinal T cells from counterparts in peripheral blood and revealed distinct signalling pathways for each intestinal T cell subset. Intestinal-specific T cell transcripts were enriched in GWAS risk loci for Crohn's disease, ulcerative colitis and coeliac disease, but also specific extraintestinal immune-mediated diseases, allowing prediction of novel candidate genes.

Conclusions This is the first report of transcriptomes for minimally manipulated intestinal T lymphocyte subsets in humans. We have demonstrated that careful processing of mucosal biopsies allows the generation of transcriptomes from as few as 1000 highly purified cells with minimal interindividual variation. Bioinformatic integration of transcriptomic data with recent GWAS data identified specific candidate genes and cell types for inflammatory pathologies.

  • IBD
  • Intestinal T Cells
  • Genetic Polymorphisms
  • Coeliac Disease
  • Immune Response

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/3.0/

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