Details

Autor(en) / Beteiligte

• Yang, Jennie H M
• Cutler, Antony J
• Ferreira, Ricardo C
• Reading, James L
• Cooper, Nicholas J
• Wallace, Chris
• Clarke, Pamela
• Smyth, Deborah J
• Boyce, Christopher S
• Gao, Guo-Jian
• Todd, John A
• Wicker, Linda S
• Tree, Timothy I M

Titel

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

Ist Teil von

• Diabetes (New York, N.Y.), 2015-11, Vol.64 (11), p.3891-3902

Ort / Verlag

United States: American Diabetes Association

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.