High-Throughput Sequencing of Islet-Infiltrating Memory CD4+ T Cells Reveals a Similar Pattern of TCR Vβ Usage in Prediabetic and Diabetic NOD Mice

Autoreactive memory CD4(+) T cells play a critical role in the development of type 1 diabetes, but it is not yet known how the clonotypic composition and TCR beta repertoire of the memory CD4(+) T cell compartment changes during the transition from prediabetes to diabetes. In this study, we used high-throughput sequencing to analyze the TCR beta repertoire of sorted islet-infiltrating memory CD4(+)CD44(high) T cells in 10-week-old prediabetic and recently diabetic NOD mice. We show that most clonotypes of islet-infiltrating CD4(+)CD44(high) T cells were rare, but high-frequency clonotypes were significantly more common in diabetic than in prediabetic mice. Moreover, although the CD4(+)CD44(high) TCR beta repertoires were highly diverse at both stages of disease development, dominant use of TRBV1 (V beta 2), TRBV13-3 (V beta 8.1), and TRBV19 (V beta 6) was evident in both prediabetic and diabetic mice. Our findings strongly suggest that therapeutic targeting of cells specifically expressing the dominant TCR beta might reduce pancreatic infiltration in prediabetic mice and attenuate the progression to diabetes.