Dataset Information

Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes.

ABSTRACT: Defective immune homeostasis in the balance between FOXP3+ regulatory T cells (Tregs) and effector T cells is a likely contributing factor in the loss of self-tolerance observed in type 1 diabetes (T1D). Given the importance of interleukin-2 (IL-2) signaling in the generation and function of Tregs, observations that polymorphisms in genes in the IL-2 pathway associate with T1D and that some individuals with T1D exhibit reduced IL-2 signaling indicate that impairment of this pathway may play a role in Treg dysfunction and the pathogenesis of T1D. Here, we have examined IL-2 sensitivity in CD4+ T-cell subsets in 70 individuals with long-standing T1D, allowing us to investigate the effect of low IL-2 sensitivity on Treg frequency and function. IL-2 responsiveness, measured by STAT5a phosphorylation, was a very stable phenotype within individuals but exhibited considerable interindividual variation and was influenced by T1D-associated PTPN2 gene polymorphisms. Tregs from individuals with lower IL-2 signaling were reduced in frequency, were less able to maintain expression of FOXP3 under limiting concentrations of IL-2, and displayed reduced suppressor function. These results suggest that reduced IL-2 signaling may be used to identify patients with the highest Treg dysfunction and who may benefit most from IL-2 immunotherapy.

SUBMITTER: Yang JH

PROVIDER: S-EPMC4975524 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Publications

Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes.

Yang Jennie H M JH Cutler Antony J AJ Ferreira Ricardo C RC Reading James L JL Cooper Nicholas J NJ Wallace Chris C Clarke Pamela P Smyth Deborah J DJ Boyce Christopher S CS Gao Guo-Jian GJ Todd John A JA Wicker Linda S LS Tree Timothy I M TI

Diabetes 20150729 11

Defective immune homeostasis in the balance between FOXP3+ regulatory T cells (Tregs) and effector T cells is a likely contributing factor in the loss of self-tolerance observed in type 1 diabetes (T1D). Given the importance of interleukin-2 (IL-2) signaling in the generation and function of Tregs, observations that polymorphisms in genes in the IL-2 pathway associate with T1D and that some individuals with T1D exhibit reduced IL-2 signaling indicate that impairment of this pathway may play a ro ...[more]

PMID: 26224887

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Project description:Modern wheat (Triticum aestivum L.) cultivars have a free-threshing habit, which allows for easy manual or mechanical threshing. However, when harvesting is delayed or extreme weather events occur at harvest time, grain shattering can cause severe loss of harvestable yield. In the past, grain size was considered a predisposing factor as large, plump kernels can lead to buckling and breaking of the outer glume, but the correlation between glume strength and shattering is not strong in modern wheat, and it is hypothesised that there may be other genetic mechanisms. Data from two bi-parent populations and a wheat diversity panel were analyzed to explore the underlying genetic basis for grain shattering observed in multiple field experiments through quantitative trait loci (QTL) analysis. Grain shattering had a significant and negative association with grain yield, irrespective of populations and environments. The correlation with plant height was positive in all populations, but correlations with phenology were population specific, being negative in the diversity panel and the Drysdale × Waagan population, and positive in the Crusader × RT812 population. In the wheat diversity panel, allelic variations at well-known major genes (Rht-B1, Rht-D1 and Ppd-D1) showed minimal association with grain shattering. Instead, the genome-wide analysis identified a single locus on chromosome 2DS, which explained 50% of the phenotypic variation, and mapping to ~ 10 Mb from Tenacious glume (Tg) gene. In the Drysdale × Waagan cross, however, the reduced height (Rht) genes showed major effects on grain shattering. At the Rht-B1 locus, the Rht-B1b allele was associated with 10.4 cm shorter plant height, and 18% decreased grain shattering, whereas Rht-D1b reduced plant height by 11.4 cm and reduced grain shattering by 20%. Ten QTL were detected in the Crusader × RT812, including a major locus detected on the long arm of chromosome 5A. All the QTL identified in this population were non-pleiotropic, as they were still significant even after removing the influence of plant height. In conclusion, these results indicated a complex genetic system for grain shattering in modern wheat, which varied with genetic background, involved pleiotropic as well as independent gene actions, and which might be different from shattering in wild wheat species caused by major domestication genes. The influence of Rht genes was confirmed, and this provides valuable information in breeding crops of the future. Further, the SNP marker close to Tg on chromosome 2DS should be considered for utility in marker-assisted selection.

Dataset Information

Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes.

Publications

Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes.

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