Oral Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

The impact of IL-2 signalling on regulatory T cell function in type 1 diabetes (T1D) (#207)

Jennie HM Yang 1 , John A Todd 2 , Linda S Wicker 2 , Timothy IM Tree 1
  1. Department of Immunobioloy, King's College London, London, United Kingdom
  2. Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, United Kingdom

Mechanisms leading to T1D depend on a complex combination of genetics and cellular elements that result in the breakdown of peripheral tolerance, including defective function of FOXP3+ Tregs. Given the importance of IL-2 signalling pathway in the generation and function of Tregs, observations that polymorphisms in genes in the IL-2 pathway, including IL2, IL2RA and PTPN2, associate with T1D and that patients with T1D have reduced IL-2 signalling in CD4+ T cells suggest that impairment of this pathway may play a role in Treg dysfunction and the pathogenesis of T1D. Here, we have assessed IL-2 responsiveness in 78 long-standing T1D patients at two time points by measuring STAT5 phosphorylation in CD4+ T cell subsets and utilising fluorescent cell barcoding technique to minimise staining variability. Whereas we observed extensive inter-individual variation, IL-2 responsiveness was highly reproducible between bleeds from an individual (R2>0.34,P<1x10-4) suggesting it may be under genetic control. Indeed, we found that the T1D-associated IL2RA SNP (rs12722495) correlated with reduced CD25 expression (P=1x10-4) and diminished IL-2 signalling (P=4x10-3) in memory CD4+ T cells. In addition, reduced IL-2 signalling was also found to be associated with patients carrying T1D risk alleles at PTPN2 SNPs, rs45450798 and rs478582 (P<0.03). Subgroups of patients representing extremes of IL-2 signalling (high and low) were recalled for in-depth analyses of Treg phenotype and function. Patients with low IL-2 signalling were found to have reduced Treg CD25 expression and a significantly lower frequency of circulating Tregs. Furthermore, Tregs of patients with reduced IL-2 signalling failed to maintain expression of FOXP3 when in cultured with sub-optimal concentrations of IL-2. These results suggest that diminished IL-2 signalling is a feature of a subgroup of individuals with T1D and may act as a biomarker to identify patients with Treg dysfunction who may benefit from low dose IL-2 immunotherapy.