Other ; This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pmed.1002139 ; Abstract ; $\textbf{Background}$ Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4$^+$ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4$^+$ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. $\textbf{Methods and Findings}$ To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3$^+$ CD4$^+$ CD25$^{high}$CD127$^{low}$) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five preassigned single doses from 0.04 × 10$^6$ to 1.5 × 10$^6$ IU/m$^2$ , in order to model the doseresponse curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population ($n$ = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 10$^6$ IU/m$^2$ (standard error [SE] = 0.078, 95% CI = −0.052, 0.254) and 0.497 × 10$^6$ IU/m$^2$ (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015–0.24 IU/ml), even at the lowest doses (0.040 × 10$^6$ and 0.045 × 10$^6$ IU/m$^2$ ) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%–48.2%, $n$ = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the $β$ chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%–85.5%, $n$ = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. $\textbf{Conclusions}$ The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2–3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%–50%, with the eventual goal of preventing T1D. $\textbf{Trial Registration}$ ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735 ; Other ; JDRF (Grant ID: 9-2011-253), Wellcome Trust (Grant IDs: 091157, 089989, 097997/Z/11/Z), National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, European Union’s 7th Framework Programme (FP7/2007-2013) (Grant ID: 241447 (NAIMIT)), Sir Jules Thorn Charitable Trust (Grant ID: 13/JTA), Medical Research Council (Grant ID: G0800860), The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (Grant ID: 100140)