# Multi-centered T cell repertoire profiling identifies alterations in the immune repertoire of individuals with inflammatory bowel disease across different disease stages

## TL;DR

This study profiles T cell repertoires in inflammatory bowel disease patients to identify immune alterations across disease stages, revealing potential new therapeutic targets.

## Contribution

The study identifies T cell clonotypes associated with IBD at different stages and validates their robustness across multiple cohorts.

## Key findings

- Expansion of Crohn’s-associated invariant T cells was replicated across three IBD cohorts.
- Clonotypes associated with IBD were identified at diagnosis and decades post-diagnosis.
- A set of clonotypes was found to be consistently associated with IBD regardless of disease stage.

## Abstract

Inflammatory bowel disease (IBD) is an incurable immune-mediated inflammatory disease, affecting the gut with a high rate of primary- and secondary- loss-of-response to therapy. By investigating the T cell receptor repertoire of individuals with IBD, novel therapeutic and preventive strategies can be identified, and a better understanding of IBD can be obtained.

To identify and validate T cell clonotypes implicated in the pathogenesis of IBD, we profiled the T cell receptor alpha (TRA) repertoire of three cohorts containing treatment-naive, treated individuals, and individuals living with the disease for >20 years, resulting in an exhaustive dataset containing the TRA repertoire of 1,732 individuals.

Using the generated datasets, we were able to replicate previous findings describing the expansion of Crohn’s-associated invariant T (CAIT) cells in individuals with Crohn’s disease (CD) in the three cohorts. Using a hypothesis-free statistical testing framework, we identified clonotypes that were associated with the disease at its different stages, e.g., at the time of diagnosis and decades post-diagnosis. By conducting a meta-analysis across the three cohorts, we were able to identify a set of clonotypes that were associated with the disease regardless of its stage. We validated our findings in a previously published independent test dataset from a German cohort, showing the robustness of the identified clonotypes.

The identified clonotypes are novel therapeutic targets to treat IBD, for example, through targeted depletion. By identifying antigens recognized by these T cells, a better understanding of the etiopathology of IBD, particularly CD, can be obtained.

The online version contains supplementary material available at 10.1186/s13073-025-01575-w.