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Genomic profiling of intestinal T-cell receptor repertoires in inflammatory bowel disease

Genes & Immunity volume 21, pages 109–118 (2020)Cite this article

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Abstract

Growing evidence shows that inflammatory bowel disease (IBD) results from dysregulation of immune responses to gut microbes. T-cell receptors (TCRs) expressed on the T-cell surface play critical roles in discriminating pathogens from commensal intestinal microorganisms at the front line of the adaptive immune system. The breakdown of this interaction may trigger persistent inflammatory responses to gut bacteria, resulting in IBD. Taking advantage of high-throughput sequencing, we developed an integrated approach to dissect the intestinal TCR repertoires underlying IBD by collecting peripheral blood and inflamed intestine from the same set of 11 IBD cases. The intestinal TCR repertoires show lower clonotype diversity (p < 0.05) and stronger clonal expansion (p < 0.02) than those in the blood. This pattern becomes more profound in TCRs unique to the inflamed tissue compared with shared TCRs. Our approach further identified the increased usage of TRAV12-3 (false discovery rate, FDR < 5%), which biases its choices of J genes towards the reduction of TRAJ37 and TRAJ43 usage (FDR < 20%) in the inflamed intestine. Our genomic profiling suggests that this selective bias of V and J gene usage may lead to a loss of diversity in the intestinal TCR repertoires and result in mucosal inflammation in IBD.

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Fig. 1: Comparison of the diversity in TCR repertoires between blood and inflamed intestinal tissue.
Fig. 2: Proportion of TCR-α or TCR-β clonotypes assigned into four different classes in the blood (transparent colors) and the inflamed tissue (solid colors).
Fig. 3: Clonality scores of TCR-α and TCR-β chains across the four different classes of TCR clonotypes.
Fig. 4: Comparison of gene usage between inflamed tissue and blood in the Uni-Pri class.

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Acknowledgements

We sincerely thank all IBD patients who participated in this study. We would like to thank the M.Sc. Molecular Medicine course, School of Medicine, Trinity College Dublin, for the encouragement and the partial financial support. This study was supported by grants from institutional supports that include Wellcome Trust Institutional Strategic Support Fund to Trinity College Dublin, Trinity Translational Medicine Institute Collaborative Pilot Study Awards, and Dean’s Research Initiatives Fund 2016–17.

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Authors and Affiliations

  1. School of Medicine, Trinity College Dublin, Dublin, Ireland

    Keerthana Saravanarajan & Shigeki Nakagome

  2. Trinity Academic Gastroenterology Group, Department of Clinical Medicine Tallaght Hospital, Trinity College Dublin, Dublin, Ireland

    Atiyekeogbebe Rita Douglas, Mohd Syafiq Ismail, Joseph Omorogbe, Serhiy Semenov, Greg Muphy, Fiona O’Riordan & Deirdre McNamara

  3. Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland

    Shigeki Nakagome

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Saravanarajan, K., Douglas, A.R., Ismail, M.S. et al. Genomic profiling of intestinal T-cell receptor repertoires in inflammatory bowel disease. Genes Immun 21, 109–118 (2020). https://doi.org/10.1038/s41435-020-0092-x

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