Quantitative V gene–targeted T cell receptor sequencing as a biomarker in type 1 diabetes
Laurie G. Landry, Kristen L. Wells, Amanda M. Anderson, Kristen R. Miller, Kenneth L. Jones, Aaron W. Michels, Maki Nakayama
Laurie G. Landry, Kristen L. Wells, Amanda M. Anderson, Kristen R. Miller, Kenneth L. Jones, Aaron W. Michels, Maki Nakayama
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Research Article Immunology

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

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.

Authors

Laurie G. Landry, Kristen L. Wells, Amanda M. Anderson, Kristen R. Miller, Kenneth L. Jones, Aaron W. Michels, Maki Nakayama

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Figure 4

Longitudinal analysis of NY8.3 α clonotypes in the peripheral blood.

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Longitudinal analysis of NY8.3 α clonotypes in the peripheral blood. TCR...
TCR α clonotypes containing TRAV16 in blood samples of wild-type NOD (n = 9) and insulin-KO NOD mice (n = 7) were determined using TRAV16-targeted sequencing. The average frequency of public NY8.3 (A) and extended NY8.3 (B) of wild-type NOD (red) and insulin-KO NOD (blue) is plotted for blood samples taken from 5 to 20 weeks of age. Blood samples taken at the diabetic end sampling point for each mouse are included in the next age set. The highest values of individual mice during the study period are plotted for public NY8.3 (C) and extended NY8.3 (D). The dashed line is the cutoff value determined by the 99th percentile of highest values in insulin-KO mice. White triangle symbols represent data from NOD mice that did not develop diabetes during the study period. Fisher’s exact tests were conducted to test for differences in >0.55% public NY8.3 (C) (P = 0.03) and >0.7% extended NY8.3 (D) (P = 0.003) between wild-type NOD and insulin-KO NOD.