Dominant TNFα and impaired IL-2 cytokine profiles of CD4+ T cells from children with type-1 diabetes

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Abstract

Aberrantly activated CD4+T memory cells play a central role in the development of type-1-diabetes. Interleukin-7 promotes generation of autoimmune memory T cells and increased Interleukin-7 availability is associated with type-1-diabetes susceptibility. T-cell-mediated immune pathology at onset of type-1-diabetes is well defined, but characteristics of long-term symptomatic disease stages remain largely elusive. In the present study, memory CD4+T-cell activation and cytokine expression as well as sensitivity to Interleukin-7in vitrowere compared between patients with type-1-diabetes at clinical onset (n = 25), long-term symptomatic disease (median duration 4.5 years,n = 19) and matched healthy controls (n = 21). T-cell responses of type-1-diabetes patients were characterized by higher frequencies of cytokine and activation marker expressing CD4+memory T cells as compared to healthy controls. Notably, correction for individual cytokine expression levels revealed qualitative differences of cytokine profiles characterized by significantly increased TNFα and decreased IL-2-expressing T-cell proportions in long-term type-1-diabetes patients. IL-7-mediated T-cell co-stimulation induced quantitative and qualitative cytokine expression differences highly similar to type-1-diabetes-specific profiles. In addition, CD4+memory T cells from children with long-term type-1-diabetes were more sensitive toin vitroIL-7 co-stimulation. Global transcriptome analysis revealed IL-7 induced expression differences of CD4+T cells, including increased IL-2R expression and effects on subsequent T-cell receptor activation. We conclude that long-term symptomatic type-1-diabetes patients differed in memory T-cell cytokine profiles and Interleukin-7 co-stimulation. Regulation of IL-2 expression and sensitivity are affected with possible consequences for disease course and severity at long-term type-1-diabetes stages.

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