title: Human group3 innate lymphoid cells express DR3 and respond to TL1A with enhanced IL-22 production and IL-2-dependent proliferation.
abstract: Death receptor 3 (DR3, TNFRSF25) is expressed by activated lymphocytes and signaling by its ligand, TL1A, enhances cytokine expression and proliferation. Recent studies show that DR3 is also present on murine type 2 innate lymphoid cells (ILC2s). Here, we show that DR3 is expressed by IL-22-producing human group 3 innate lymphoid cells (ILC3s). Stimulation of ILC3s with exogenous TL1A alone had no impact on cytokine production or proliferation. Addition of TL1A to IL-1β + IL-23 significantly enhanced the amount IL-22 produced by ILC3s as well as the percentage IL-22- and IL-8-producing cells. Addition of TL1A to IL-1β + IL-23 also augmented ILC3 proliferation. Mechanistically, this occurred through the upregulation of CD25 and responsiveness to IL-2 stimulation. The combination of TL1A, IL-1β+ IL-23, and IL-2 expanded ILC3s while IL-1β+ IL-23 did not increase proliferation above controls. After 2 weeks of expansion, ILC3s maintained their phenotype, transcription factor expression, and function (IL-22 production). These findings identify DR3 as a costimulatory molecule on ILC3s that could be exploited for ex vivo expansion and clinical use.
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, USA.|Cancer Research Institute, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: Yong-Oon
authors.initials: YO
authors.lastname: Ahn
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Weeres
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, USA.
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Neulen
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: Jahyang
authors.initials: J
authors.lastname: Choi
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Kang
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine and Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: Dae Seog
authors.initials: DS
authors.lastname: Heo
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bergerson
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Department of Medicine, Division of Blood and Marrow Transplantation, University of Minnesota, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D007113:Immunity, Innate; D053583:Interleukin-1beta / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D053760:Interleukin-23 Subunit p19 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D007378:Interleukins / Q000276:immunology*; D008214:Lymphocytes / Q000145:classification / Q000276:immunology*; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000276:immunology*; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000276:immunology / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects* / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D053583:Interleukin-1beta; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053760:Interleukin-23 Subunit p19; D016209:Interleukin-8; D007378:Interleukins; D053219:Receptors, Tumor Necrosis Factor, Member 25; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D000097043:Interleukin-22; C508606:CXCL8 protein, human; C508585:IL1B protein, human; C508594:IL2 protein, human; C508840:IL23A protein, human; C508017:IL2RA protein, human; C506033:TNFRSF25 protein, human; C117026:TNFSF15 protein, human
keywords: DR3; Human; IL-22; ILC3; TL1A