Comment on Yang et al. Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes. Diabetes 2015;64:3891–3902

Natural Variation in Interleukin-2 Sensitivity Influences Regulator y T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes. Diabetes 2015;64:3891-3902 Sanja Glisic 1 Soumitra Ghosh 0 e - L E T T E R S - C O M M E N T S A N D R E S P O N S E S 0 Target Sciences , GlaxoSmithKline, King of Prussia, PA 1 Hematogenix Laboratory Services , Tinley Park, IL - We appreciate the work of Yang et al. ( 1 ) in clearly defining two diametrically opposite groups of interleukin (IL)-2 responders among subjects with type 1 diabetes (T1D). Their finding was correlated with regulatory T-cell (Treg) function, allowing for the stratification of T1D subjects prior to potential low-dose IL-2 therapy. They also challenged Tregs to low IL-2 in vitro and explored differential Treg apoptosis between these two strata. Specifically, they investigated Treg apoptosis primarily in long-standing T1D, finding no difference. They cited our articles as showing such a difference and implicate cryopreservation or differences in culture conditions as possible explanations for the discrepancies between our two studies. We would like to point out that we investigated phenotype differences in Treg apoptosis, and our initial work was not stratified on IL-2 response ( 2 ). We investigated subjects with newly diagnosed T1D (NDT1D) within 1 year of diagnosis and found significantly enhanced, spontaneous Treg apoptosis compared with both control and long-standing T1D subjects. Increased apoptosis was also found in at-risk (multiple autoantibody-positive) first-degree relatives of NDT1D subjects. All analyses were performed on fresh, FACS-sorted cells within 1 h after isolation. Only later did we test the effect of IL-2 deprivation on Tregs, but isolated from normal subjects, again without stratification ( 3 ). On the basis of our work and the present complementary, more comprehensive work of Yang et al. ( 1 ), we agree that NDT1D subjects would benefit greatly from low doses of IL-2, decreasing Treg apoptosis, improving function, and possibly increasing Treg numbers, which would slow b-cell destruction. We also support their call for more research in this area. Duality of Interest. No potential conflicts of interest relevant to this article were reported. 1. Yang JHM , Cutler AJ , Ferreira RC , et al. Natural variation in interleukin-2 sensitivity influences regulatory T-cell frequency and function in individuals with long-standing type 1 diabetes . Diabetes 2015 ; 64 : 3891 - 3902 2. Glisic-Milosavljevic S , Waukau J , Jailwala P , et al. At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD41CD251 T-cell fraction . PLoS One 2007 ; 2 : e146 3. Jailwala P , Waukau J , Glisic S , et al. Apoptosis of CD41 CD25(high) T cells in type 1 diabetes may be partially mediated by IL-2 deprivation . PLoS One 2009 ; 4 : e6527 (...truncated)