title: An IL-2 paradox: blocking CD25 on T cells induces IL-2-driven activation of CD56(bright) NK cells.
abstract: Daclizumab (Dac), an Ab against the IL-2R alpha-chain, inhibits brain inflammation in patients with multiple sclerosis, while expanding CD56(bright) immunoregulatory NK cells in vivo. We hypothesized that this unexpected expansion is paradoxically IL-2 driven; caused by the increased availability of T cell-derived IL-2 for NK cell signaling. To this end, we performed ex vivo functional analyses of CD56(bright) NK cells and T cells from patients in clinical trials with Dac. We developed in vitro models to investigate mechanisms for ex vivo observations. We observed that Dac treatment caused decreased numbers and proliferation of FoxP3(+) T regulatory cells (Tregs), a model T cell population known to be dependent on IL-2 for proliferation and survival. As anticipated, Dac therapy inhibited IL-2 signaling in all T cells; however, we also observed functional adaptation of T cells to low IL-2 signal in vivo, characterized by the concomitant enhancement of IL-7 signaling on all T cells and parallel increase of CD127 expression by Tregs. In contrast, IL-2 signaling on CD56(bright) NK cells was not inhibited by Dac and their in vivo proliferation and cytotoxicity actually increased. Mechanistic studies indicated that the activation of CD56(bright) NK cells was likely IL-2 driven, as low doses of IL-2, but not IL-15, mimicked this activation in vitro. Our study provides insight into the role that IL-2 and CD25 play in functional regulation of two important immunoregulatory cell populations in humans: FoxP3(+) Tregs and CD56(bright) NK cells.
authors.affiliation: Neuroimmunology Branch, National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jayne F
authors.initials: JF
authors.lastname: Martin
authors.forename: Justin S A
authors.initials: JS
authors.lastname: Perry
authors.forename: Neha R
authors.initials: NR
authors.lastname: Jakhete
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Bibiana
authors.initials: B
authors.lastname: Bielekova
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D019002:CD56 Antigen / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D000077561:Daclizumab; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology* / Q000378:metabolism; D015851:Interleukin-7 / Q000276:immunology / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016256:Lewis X Antigen / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019002:CD56 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D016256:Lewis X Antigen; D000077561:Daclizumab