Journal
DIABETES
Volume 53, Issue 8, Pages 1987-1994Publisher
AMER DIABETES ASSOC
DOI: 10.2337/diabetes.53.8.1987
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Funding
- NIAID NIH HHS [AI50864, U19 AI050864] Funding Source: Medline
- NIDDK NIH HHS [P01 DK053004, DK53004] Funding Source: Medline
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Negative selection of self-reactive T-cells during thymic development, along with activation-induced cell death in peripheral lymphocytes, is designed to limit the expansion and persistence of autoreactive T-cells. Autoreactive T-cells are nevertheless present, both in patients with type 1 diabetes and in at-risk subjects. By using MHC class II tetramers to probe the T-cell receptor (TcR) specificity and avidity of GAD65 reactive T-cell clones isolated from patients with type 1 diabetes, we identified high-avidity CD4(+) T-cells in peripheral blood, coexisting with low-avidity cells directed to the same GAD65 epitope specificity. A variety of cytokine patterns was observed, even among T-cells with high MHC-peptide avidity, and the clones utilize a biased set of TcR genes that favor two combinations, Valpha12-beta5.1 and Valpha17-Vbeta4. Presence of these high-avidity TcRs indicates a failure to delete autoreactive T-cells that likely arise from oligoclonal expansion in response to autoantigen exposure during the progression of type 1 diabetes.
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