Ontology highlight
ABSTRACT: Objective
We have previously reported a highly diabetogenic CD8 T-cell clone, G9C8, in the nonobese diabetic (NOD) mouse, specific to low-avidity insulin peptide B15-23, and cells responsive to this antigen are among the earliest islet infiltrates. We aimed to study the selection, activation, and development of the diabetogenic capacity of these insulin-reactive T-cells.Research design and methods
We generated a T-cell receptor (TCR) transgenic mouse expressing the cloned TCR Valpha18/Vbeta6 receptor of the G9C8 insulin-reactive CD8 T-cell clone. The mice were crossed to TCRCalpha-/- mice so that the majority of the T-cells expressed the clonotypic TCR, and the phenotype and function of the cells was investigated.Results
There was good selection of CD8 T-cells with a predominance of CD8 single-positive thymocytes, in spite of thymic insulin expression. Peripheral lymph node T-cells had a naïve phenotype (CD44lo, CD62Lhi) and proliferated to insulin B15-23 peptide and to insulin. These cells produced interferon-gamma and tumor necrosis factor-alpha in response to insulin peptide and were cytotoxic to insulin peptide-coated targets. In vivo, the TCR transgenic mice developed insulitis but not spontaneous diabetes. However, the mice developed diabetes on immunization, and the activated transgenic T-cells were able to transfer diabetes to immunodeficient NOD.scid mice.Conclusions
Autoimmune CD8 T-cells responding to a low-affinity insulin B-chain peptide escape from thymic negative selection and require activation in vivo to cause diabetes.
SUBMITTER: Wong FS
PROVIDER: S-EPMC2671054 | biostudies-literature | 2009 May
REPOSITORIES: biostudies-literature
Diabetes 20090210 5
<h4>Objective</h4>We have previously reported a highly diabetogenic CD8 T-cell clone, G9C8, in the nonobese diabetic (NOD) mouse, specific to low-avidity insulin peptide B15-23, and cells responsive to this antigen are among the earliest islet infiltrates. We aimed to study the selection, activation, and development of the diabetogenic capacity of these insulin-reactive T-cells.<h4>Research design and methods</h4>We generated a T-cell receptor (TCR) transgenic mouse expressing the cloned TCR Val ...[more]