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

Abstract

IntroductionThe dysregulated immune-response in Crohns 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 Crohns disease. MethodsWe performed TCR and TCR{beta} sequencing on peripheral flow-sorted CD4+ memory gut- homing (integrin4{beta}7+), non-gut-homing (integrin4{beta}7-), and regulatory T-cells (Tregs) from Dutch monozygotic Crohns disease concordant twins (N=8), monozygotic Crohns 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 Crohns disease-related TCRs. ResultsOverall diversity and clonality was comparable between Crohns disease patients, healthy cotwins and healthy controls. Comparing T-cell subsets, a decreased diversity and increased clonality was observed for Tregs. Concordant Crohns 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 Crohns disease. The identified Crohns disease-related TCR signatures have not previously been described in relation to Crohns disease, and have thus far mostly unknown antigen specificity. ConclusionsIncreased overlap in the TCR repertoires of monozygotic twin pairs concordant for Crohns disease suggest that (antigen-driven) skewing of the TCR repertoire could play a role in the pathophysiology of Crohns disease. The identified TCR-based Crohns disease signatures are prime targets for further study into the pathogenesis of Crohns disease.