Clonal overlap and convergent clustering of T-cell receptor signatures in Crohn’s disease in monozygotic twins
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Introduction
The dysregulated immune-response in Crohn’s disease might result from disturbances in the T-cell receptor (TCR) repertoire. To investigate this hypothesis, we compared the peripheral TCR repertoire within T-cell subsets in twin pairs, concordant and discordant for Crohn’s disease.
Methods
We performed TCRα and TCRβ sequencing on peripheral flow-sorted CD4+ memory gut- homing (integrinα4β7+), non-gut-homing (integrinα4β7-), and regulatory T-cells (Tregs) from Dutch monozygotic Crohn’s disease concordant twins (N=8), monozygotic Crohn’s disease discordant twins (N=8), and healthy controls (N=4). TCR diversity and clonality, overlap between individuals, convergence and enrichment, and clustering of the TCR repertoire was studied and compared to previously reported Crohn’s disease-related TCRs.
Results
Overall diversity and clonality was comparable between Crohn’s disease patients, healthy cotwins and healthy controls. Comparing T-cell subsets, a decreased diversity and increased clonality was observed for Tregs. Concordant Crohn’s disease twins had an increased overlap in TCRs for Tregs and CD4+ memory gut-homing T-cells. Using TCR convergence, enrichment and subsequent clustering analyses, we identified eight clusters of TCRs potentially related with Crohn’s disease. The identified Crohn’s disease-related TCR signatures have not previously been described in relation to Crohn’s disease, and have thus far mostly unknown antigen specificity.
Conclusions
Increased overlap in the TCR repertoires of monozygotic twin pairs concordant for Crohn’s disease suggest that (antigen-driven) skewing of the TCR repertoire could play a role in the pathophysiology of Crohn’s disease. The identified TCR-based Crohn’s disease signatures are prime targets for further study into the pathogenesis of Crohn’s disease.
