title: Dysregulation of regulatory CD56(bright) NK cells/T cells interactions in multiple sclerosis.
abstract: Recent evidence has shown that CD56(bright) NK cells, a subset of NK cells abundant in lymph nodes, may have an immunoregulatory function. In multiple sclerosis (MS), expansion of CD56(bright) NK cells has been associated to successful response to different treatments and to remission of disease during pregnancy; how whether they exert immunoregulation in physiologic conditions and whether this is impaired in MS is not known. We dissected the immunoregulatory role of CD56(bright) NK cells function in healthy subjects (HS) and compared it with that of untreated MS subjects or patients with clinically isolated syndrome suggestive of MS (CIS). We found that CD56(bright) NK cells from HS acquire, upon inflammatory cues, the capability of suppressing autologous CD4+T cell proliferation through direct cytotoxicity requiring engagement of natural cytotoxicity receptors (NCRs) and secretion of granzyme B. CD56(bright) NK cells from patients with MS/CIS did not differ in frequency and share a similar phenotype but displayed a significantly lower ability to inhibit autologous T cell proliferation. This impairment was not related to deficient expression of NCRs or granzyme B by CD56(bright) NK cells, but to increased HLA-E expression on T cells from MS/CIS subjects, which could enhance the inhibitory effect mediated by NKG2A that is homogeneously expressed on CD56(bright) NK cells. The defect in controlling autologous T cells by CD56(bright) NK cells in MS/CIS might contribute to the excess of autoimmune response that is associated to disease development.
authors.affiliation: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Largo Daneo 3, 16132 Genova, Italy; Centre of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV, 9, 1612 Genova, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Laroni
authors.affiliation: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Largo Daneo 3, 16132 Genova, Italy.
authors.forename: Eric
authors.initials: E
authors.lastname: Armentani
authors.affiliation: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Largo Daneo 3, 16132 Genova, Italy.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kerlero de Rosbo
authors.affiliation: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Largo Daneo 3, 16132 Genova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Ivaldi
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV, 9, 1612 Genova, Italy; Department of Experimental Medicine, University of Genova, Via Leon Battista Alberti, 2, 16132 Genova, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Marcenaro
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV, 9, 1612 Genova, Italy; Department of Experimental Medicine, University of Genova, Via Leon Battista Alberti, 2, 16132 Genova, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Sivori
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Roopali
authors.initials: R
authors.lastname: Gandhi
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Partners MS Center, Brigham and Women's Hospital and Harvard Medical School, 1 Brookline Place #225, Brookline, MA 02445, USA.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
authors.affiliation: Centre of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV, 9, 1612 Genova, Italy; Department of Experimental Medicine, University of Genova, Via Leon Battista Alberti, 2, 16132 Genova, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
authors.affiliation: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Largo Daneo 3, 16132 Genova, Italy; Centre of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV, 9, 1612 Genova, Italy.
authors.forename: Giovanni L
authors.initials: GL
authors.lastname: Mancardi
authors.affiliation: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Largo Daneo 3, 16132 Genova, Italy; Centre of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV, 9, 1612 Genova, Italy. Electronic address: auccelli@neurologia.unige.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Uccelli
mesh_terms: D000328:Adult; D019002:CD56 Antigen / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology*; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D053804:Granzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000276:immunology / Q000378:metabolism; D055629:Natural Cytotoxicity Triggering Receptor 2 / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: D019002:CD56 Antigen; C527085:KLRK1 protein, human; C112837:NCR2 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D055629:Natural Cytotoxicity Triggering Receptor 2; D053804:Granzymes
keywords: CD56(bright) NK cells; Innate immune cells; Multiple sclerosis; NK cells