High-throughput sequencing reveals restricted TCR V? usage and public TCR? clonotypes among pancreatic lymph node memory CD4(+) T cells and their involvement in autoimmune diabetes.

ABSTRACT: Islet-reactive memory CD4(+) T cells are an essential feature of type 1 diabetes (T1D) as they are involved in both spontaneous disease and in its recurrence after islet transplantation. Expansion and enrichment of memory T cells have also been shown in the peripheral blood of diabetic patients. Here, using high-throughput sequencing, we investigated the clonal diversity of the TCR? repertoire of memory CD4(+) T cells in the pancreatic lymph nodes (PaLN) of non-obese diabetic (NOD) mice and examined their clonal overlap with islet-infiltrating memory CD4T cells. Both prediabetic and diabetic NOD mice exhibited a restricted TCR? repertoire dominated by clones expressing TRBV13-2, TRBV13-1 or TRBV5 gene segments. There is a limited degree of TCR? overlap between the memory CD4 repertoire of PaLN and pancreas as well as between the prediabetic and diabetic group. However, public TCR? clonotypes were identified across several individual animals, some of them with sequences similar to the TCRs from the islet-reactive T cells suggesting their antigen-driven expansion. Moreover, the majority of the public clonotypes expressed TRBV13-2 (V?8.2) gene segment. Nasal vaccination with an immunodominat peptide derived from the TCR V?8.2 chain led to protection from diabetes, suggesting a critical role for V?8.2(+) CD4(+) memory T cells in T1D. These results suggest that memory CD4(+) T cells bearing limited dominant TRBV genes contribute to the autoimmune diabetes and can be potentially targeted for intervention in diabetes. Furthermore, our results have important implications for the identification of public T cell clonotypes as potential novel targets for immune manipulation in human T1D.

SUBMITTER: Marrero I 

PROVIDER: S-EPMC6301078 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature