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

• Published in: Diabetes (New York, N.Y.) Vol. 64; no. 11; pp. 3891 - 3902
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.11.2015
• Subjects: Cytokines; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Genotype; Homeostasis; Humans; Immunotherapy; Interleukin-2 - pharmacology; Interleukin-2 Receptor alpha Subunit - genetics; Phosphorylation; Polymorphism; Polymorphism, Single Nucleotide; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics; Signal transduction; Signal Transduction - genetics; T cell receptors; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - physiology
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db15-0516

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.