Multi-centered T cell repertoire profiling identifies alterations in the immune repertoire of individuals with inflammatory bowel disease across different disease stages
Largest-to-date T-cell receptor (TCR) alpha profiling across three different cohorts with inflammatory bowel diseases, identifies robust sets of disease-associated clonotypes and proposing a potential new therapeutic and etiologic leads.
Inflammatory bowel disease (IBD) remains incurable, and many individuals experience primary non-response or loss-of-response to existing therapies. In a new study published in Genome Medicine, researchers report that large-scale profiling of the T cell receptor alpha (TRA) repertoire across multiple international cohorts can uncover reproducible, disease-associated T cell “clonotypes” associated with Crohn’s disease (CD) and ulcerative colitis (UC) – including clonotypes that persist across disease stages and treatment histories.
A multi-cohort immune repertoire map of IBD
The team of Prof. Andre Franke, led by a postdoc, Dr. Aya Mahdy, and Dr. Hesham ElAbd (P1), analysed TRA repertoires from 1,732 individuals across three cohorts spanning distinct disease timepoints and trajectories: a population-based inception cohort with treatment-naïve and treated patients (IBSEN-III), a long-term follow-up cohort sampled 20 years post-diagnosis (IBSEN-20), and a German case-control cohort (BCBC). This design enabled side-by-side assessment of immune repertoire changes from early disease through decades of disease history. Using a hypothesis-free statistical framework to detect public (shared) clonotypes enriched in disease, the researchers replicated prior observations and identified additional CD- and UC-associated TRA sequences. A cross-cohort meta-analysis then distilled a set of clonotypes associated with disease regardless of stage and validated robustness in an independent published dataset.
CAIT cells are consistently expanded in Crohn’s disease across cohorts and disease stages. The study replicated the expansion of Crohn’s-associated invariant T (CAIT) cells in individuals with CD across all three cohorts, including treatment-naïve samples and individuals decades post-diagnosis, suggesting the signal reflects underlying disease biology rather than medication exposure.
CAIT expansion tracks clinically relevant subphenotypes. In adult CD, CAIT expansion was higher in individuals with ileal/ileocolonic involvement, associated with more severe disease behavior, and correlated with Anti-Saccharomyces cerevisiae antibodies (ASCA) positivity.
MAIT cells are reduced in the blood in IBD and are minimally influenced by treatment. The abundance of MAIT-associated TRA patterns was reduced in CD and UC compared with controls, with limited difference between treatment-naïve and treated individuals.
Meta-analysis identifies robust, shared disease-associated clonotypes. Across cohorts, the authors report a CD-associated set derived via meta-analysis (including multiple CAIT clonotypes) and UC-associated sets that differ depending on cohort composition – highlighting how study design and comparison groups can shape UC signals.
Why this matters
Therapeutic opportunities. The findings support the concept that disease-associated T cell clonotypes may be actionable targets – either through targeted depletion strategies or by using clonotypes as biomarkers to stratify patients and monitor disease biology. The research article by Mahdy and ElAbd et al, also discusses CAIT cells as a particularly promising therapeutic target because they are CD1d-restricted, and CD1d is largely monomorphic – raising the possibility of broader applicability across patients than HLA-restricted conventional T cell targets.
Clues to disease triggers. While bulk TCR sequencing does not directly identify antigens, disease-associated clonotypes can help trace the immune system’s history of antigen exposure. By focusing on stable signals like CAIT cells and other clustered clonotypes, the work provides a roadmap for future studies aimed at uncovering antigenic drivers and mechanisms in IBD – especially Crohn’s disease.
By integrating three cohorts spanning early disease, treated disease, and long-term follow-up, we identify TRA clonotypes that are reproducible across geography and disease stage. In addition, the robustness of CAIT expansion across treatment status and decades post-diagnosis suggests these cells are a stable component of Crohn’s disease biology and a compelling starting point for both therapeutic targeting and antigen discovery. [Aya Mahdy and Hesham ElAbd, Institute of Clinical Molecular Biology, University of Kiel and University-Hospital Schleswig-Holstein, Rosalind-Franklin-Str. 12, 24105 Kiel, Germany]
Publication details
Title: Multi-centered T cell repertoire profiling identifies alterations in the immune repertoire of individuals with inflammatory bowel disease across different disease stages
Journal: Genome Medicine
DOI: 10.1186/s13073-025-01575-w
About the study
This study profiled the T cell receptor alpha (TRA) repertoire from international cohorts using widely used immune repertoire sequencing approaches and statistical association testing of public clonotypes, followed by cross-cohort meta-analysis and independent validation. So, the team focused on the power of cohort design and scale.
About Genome Medicine
Genome Medicine is an open-access journal publishing research and commentary on the role of genomic and post-genomic technologies in improving human health.
