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 5

TCR sequences shared between pancreatic tissues of organ donors with or without different stages of T1D.

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TCR sequences shared between pancreatic tissues of organ donors with or ...
TCR α and β chain sequences expressed by CD4+ and CD8+ T cells in pancreatic tissues of organ donors were determined and analyzed for sharing between individual donors. (A–D) TCR clonotypes of T1D, autoantibody-positive prediabetic (AAb), and nondiabetic organ donors are shown in orange, green, and violet, and those shared between the different groups are connected by black lines. Thickness of lines represents frequency of TCR clonotypes in each donor. Shared TCR α and β chain clonotypes expressed by CD4+ T cells are shown in panels A and B, respectively, and those by CD8+ T cells are shown in panels C and D. (E–H) The numbers of CD4α (E), CD4β (F), CD8α (G), and CD8β (H) chain clonotypes shared between the groups are shown in Venn diagrams with the same color coordination used in panels A–D. (I) The numbers of α and β clonotypes expressed by CD4+ (red) and CD8+ (blue) T cells were compared by a paired, 2-tailed t test (P = 0.037). (J) The numbers of clonotypes that are exactly identical between donors and those that are clustered are shown (CD4α: red triangles, CD4β: red inverse triangles, CD8α: blue triangles, and CD8β: blue inverse triangles).