Articleshttps://doi.org/10.1038/s41591-018-0070-21UCSFDiabetesCenter,UniversityofCalifornia,SanFrancisco,SanFrancisco,CA,USA.2CentersforTherapeuticInnovation,PfizerInc.,SanFrancisco,CA,USA.3DepartmentsofMolecular&CellularPhysiologyandStructuralBiology,StanfordUniversity,Stanford,CA,USA.4StanfordCancerInstitute,StanfordUniversitySchoolofMedicine,Stanford,CA,USA.5DepartmentofPediatricImmunology,AllergyandRheumatology,UniversityofHouston,Houston,TX,USA.6BioElectronTechnologyCorporation,MountainView,CA,USA.7PandionTherapeutics,Cambridge,MA,USA.8DepartmentofMicrobiologyandImmunology,UniversityofCalifornia,SanFrancisco,SanFrancisco,CA,USA.9HowardHughesMedicalInstitute,StanfordUniversitySchoolofMedicine,Stanford,CA,USA.10ParkerInstituteforCancerImmunotherapy,SanFrancisco,CA,USA.11Theseauthorsjointlysupervisedthiswork:NatashaK.Crellin,IsaacJ.Rondon,JeffreyA.Bluestone.*e-mail:Jeff.Bluestone@ucsf.eduInterleukin-2(IL-2)istypeIcytokinethatfunctionsasamulti-lineagelymphocytegrowthfactor1–3.IL-2signalsthroughatri-mericreceptorcomprisedofIL-2Rα(CD25),IL-2Rβ(CD122)andIL-2Rγ(CD132)2–4.Thesignalingcanbeinitiatedeitherthroughthehigh-affinity(Kd≈10pM)trimericcomplexofthethreesubunitsorthroughanintermediate-affinitydimericcomplex(Kd≈1nM)withonlyIL-2RβandIL-2Rγ,withoutthenon-signalingIL-2Rαsubunit.ThetrimericIL-2RsaretypicallyexpressedathighlevelsbyTregs5,activatedTeffectors(Teffs)andILC2s6,whilethedimericformofIL-2Risexpressedmostlyonantigen-experiencedCD8+Tcellsandnaturalkiller(NK)cells7.PreviousstudiesshowedthatIL-2ishighlyflexible8,9andexistsindifferentconformationsthatfavoreitherthehigh-affinitytrimericIL-2Rorintermediate-affin-itydimericIL-2R,resultingintheactivationofdifferentimmunecells9.ThisplasticityhascomplicatedtheuseoftheapproveddrugProleukinathighdosestotreatmetastaticmelanomaandrenalcellcarcinoma10,duetotheroleofIL-2asanessentialgrowthfactorforTregs11–13.Moreover,adverseeffectsofhigh-doseIL-2therapyhavegreatlylimiteditsuse14,15.Severalstudieshaveshownthatlow-...
