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Activation of insulin-reactive CD8 T-cells for development of autoimmune diabetes.


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

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Publications

Activation of insulin-reactive CD8 T-cells for development of autoimmune diabetes.

Wong F Susan FS   Siew Lai Khai LK   Scott Gwen G   Thomas Ian J IJ   Chapman Stephen S   Viret Christophe C   Wen Li L  

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]

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