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.