title: Inhibition of LTi cell development by CD25 blockade is associated with decreased intrathecal inflammation in multiple sclerosis.
abstract: Genetic polymorphisms in the interleukin-2 receptor α (IL-2Rα) chain (CD25) locus are associated with several human autoimmune diseases, including multiple sclerosis (MS). Blockade of CD25 by the humanized monoclonal antibody daclizumab decreases MS-associated inflammation but has surprisingly limited direct inhibitory effects on activated T cells. The present study describes unexpected effects of daclizumab therapy on innate lymphoid cells (ILCs). The number of circulating retinoic acid receptor-related orphan receptor γt-positive ILCs, which include lymphoid tissue inducer (LTi) cells, was found to be elevated in untreated MS patients compared to healthy subjects. Daclizumab therapy not only decreased numbers of ILCs but also modified their phenotype away from LTi cells and toward a natural killer (NK) cell lineage. Mechanistic studies indicated that daclizumab inhibited differentiation of LTi cells from CD34⁺ hematopoietic progenitor cells or c-kit⁺ ILCs indirectly, steering their differentiation toward immunoregulatory CD56(bright) NK cells through enhanced intermediate-affinity IL-2 signaling. Because adult LTi cells may retain lymphoid tissue-inducing capacity or stimulate adaptive immune responses, we indirectly measured intrathecal inflammation in daclizumab-treated MS patients by quantifying the cerebrospinal fluid chemokine (C-X-C motif) ligand 13 and immunoglobulin G index. Both of these inflammatory biomarkers were inhibited by daclizumab treatment. Our study indicates that ILCs are involved in the regulation of adaptive immune responses, and their role in human autoimmunity should be investigated further, including their potential as therapeutic targets.
authors.affiliation: Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Justin S A
authors.initials: JS
authors.lastname: Perry
authors.forename: Sungpil
authors.initials: S
authors.lastname: Han
authors.forename: Quangang
authors.initials: Q
authors.lastname: Xu
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Herman
authors.forename: Lucy B
authors.initials: LB
authors.lastname: Kennedy
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Csako
authors.forename: Bibiana
authors.initials: B
authors.lastname: Bielekova
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D054382:Chemokine CXCL13 / Q000378:metabolism; D000077561:Daclizumab; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy*; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors*; D007694:Killer Cells, Natural; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D054382:Chemokine CXCL13; D007074:Immunoglobulin G; D053645:Interleukin-2 Receptor alpha Subunit; D050799:STAT5 Transcription Factor; D000077561:Daclizumab