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

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-7 in vitro were 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 to in vitro IL-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.

Interleukin-7 receptor α-chain haplotypes differentially affect soluble IL-7 receptor and IL-7 serum concentrations in children with type 1 diabetes

“…Bian et al described a generally high‐activation pattern of memory T cells from T1D patients. Accordingly, we demonstrated that memory T cells from symptomatic T1D patients produced generally higher cytokine levels and were more sensitive to IL‐7‐mediated T cell costimulation . IL‐7 especially promoted the effector cytokines IFNγ and TNFα in these T1D patients, whereas relative IL‐2 production was lower as compared to healthy controls .…”

“…Recently, we showed that IL‐7 differentially affected cytokine expressing T cell proportions of children with T1D in vitro . Hence, we compared IL‐7 effects on IFNγ, TNFα, and IL‐2 secretion of CD4 + and CD8 + T cells with differential IL‐7 serum levels.…”

“…Children with T1D were recruited at onset of T1D ( n = 25) or at least 6 months after clinical onset of the disease ( n = 17). Detailed study cohort characteristics were published previously . The ethics committee of the medical faculty, Heinrich‐Heine‐University Duesseldorf approved this study (ID 4844).…”

“…mIL‐7R expression was determined after overnight in vitro culture with or without recombinant human (rh)IL‐7 internalization (BioLegend, San Diego, CA, USA). Procedures, material and data analyses have been described previously . In brief, CD4 + T cells were analyzed for mIL‐7R high expressing proportions.…”

“…Intracellular T cell cytokines were measured after overnight culture with or without rhIL‐7 followed by T cell activation for 6 hours as described previously . Samples were measured by flow cytometry (LSRFortessa, BD Biosciences) and data analysis was performed using FlowJo software (Miltenyi Biotech).…”