Longitudinal TCR repertoires in ulcerative colitis patients show features distinguishing disease states

Background

Ulcerative colitis (UC) affects an estimated 10 million people worldwide. The exact etiology of the disease is unknown, but T cell dysregulation and aberrant activation is associated with UC—prompting research into T cell receptor (TCR) repertoires in UC patients. However, few studies have compared UC patients’ TCR repertoires in flare (inflamed) and remission (uninflamed) states. Moreover, this is the first dataset to our knowledge examining multiple repertoires from UC patients over time, enabling longitudinal analyses.

Methods

TCR repertoires were obtained for 21 patients across multiple timepoints, yielding a total of 58 samples. Repertoires’ clonality, diversity, overlap, and gene usage frequencies were compared across all patients. CDR3 sequences were split into K-mers (sequences of length K), and enriched K-mers in flare and remission states were identified using GLIPH2.

Results

Although repertoires vary across patients, there were significant differences in the usage of 20 Vβ genes across flare and remission states. Moreover, calculating the overlap in repertoires with enriched K-mers showed higher overlap scores than when using full TCR sequences. 622 unique enriched K-mers were identified in flare states and 495 in remission states, with only 57 overlapping between the two states.

Conclusions

Overall, these results highlight the importance of analyzing Vβ gene usage and K-mer enrichment in TCR repertoires, particularly given the lack of public clones across patient cohorts. Future studies characterizing the specific antigenic targets associated with these features will pave the way for biomarker discovery in UC.

KEY MESSAGES

• What is already known? UC is a chronic condition characterized by fluctuating periods of flares and remissions, as well as aberrant immune activity.

• What is new here? TCR repertoires were obtained from UC patients’ colonoscopies, with multiple timepoints per patient—enabling the analysis of repertoire characteristics within and across patients over time.

• How can this study help patient care? Understanding the exact immune mechanisms in UC can pave the way for biomarker discovery and advance the state of care for patients, given that current treatments are non-specific and have adverse side effects.

Summary

This article presents an analysis of T cell receptor repertoires from ulcerative colitis patient samples collected during colonoscopies, identifying genes and motifs associated with patients’ flare (inflamed) and remission (uninflamed) states.