# Quantitative V gene–targeted T cell receptor sequencing as a biomarker in type 1 diabetes

## TL;DR

This study shows how tracking specific T cell receptors in blood can help monitor and predict type 1 diabetes progression.

## Contribution

A new method using V gene–targeted TCR sequencing to identify public, disease-specific clonotypes in T1D.

## Key findings

- Public TCR clonotypes were found in both NOD mice and human T1D donors.
- TRAV16/16D-targeted sequencing detected islet-antigen-reactive TCRs in blood.
- Public TCR frequencies distinguished prediabetic from protected NOD mice.

## Abstract

Developing biomarkers to quantitatively monitor disease-specific T cell activity is crucial for assessing type 1 diabetes (T1D) progression and evaluating immunotherapies. This study presents an approach using V gene–targeted sequencing to quantify T cell receptor (TCR) clonotypes as biomarkers for pathogenic T cells in T1D. We identified “public” TCR clonotypes shared among multiple nonobese diabetic (NOD) mice and human organ donors, with a subset expressed exclusively by islet-antigen-reactive T cells in those with T1D. Employing V gene–targeted sequencing of only TCRs containing TRAV16/16D allowed quantitative detection of the public islet-antigen-reactive TCR clonotypes in peripheral blood of NOD mice. Frequencies of these public TCR clonotypes distinguished prediabetic NOD mice from those protected from diabetes. In human islets, public TCR clonotypes identical to preproinsulin-specific clones were exclusively found in T1D donors. This quantifiable TCR sequencing approach uncovered public, disease-specific clonotypes in T1D, providing biomarker candidates to monitor pathogenic T cell frequencies in blood for assessing disease activity and therapeutic response.

This study provides a proof-of-concept to utilize immune-receptor sequences to monitor antigen-specific T cells in the blood, predicting progression of autoimmune diseases.