Clonal overlap and convergent clustering of T cell receptor signatures in Crohn's disease in monozygotic twins.

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 (integrin α4β7), non-gut-homing (integrin α4β7-), 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 control subjects (n = 4). TCR diversity and clonality, overlap between individuals, convergence and enrichment, and clustering of the TCR repertoire was studied and compared with previously reportd Crohn's disease-related TCRs.

RESULTS

Overall diversity and clonality was comparable between Crohn's disease patients, healthy cotwins, and healthy control subjects. 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 8 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 thus far have 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 pathophysiology of Crohn's disease.