Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2016-05, Vol.113 (21), p.E2973-E2982
• Main Authors: Gross, Catharina C., Schulte-Mecklenbeck, Andreas, Rünzi, Anna, Kuhlmann, Tanja, Posevitz-Fejfár, Anita, Schwab, Nicholas, Schneider-Hohendorf, Tilman, Herich, Sebastian, Held, Kathrin, Konjević, Matea, Hartwig, Marvin, Dornmair, Klaus, Hohlfeld, Reinhard, Ziemssen, Tjalf, Klotz, Luisa, Meuth, Sven G., Wiendl, Heinz
• Format: Article
• Language: English
• Subjects: Antigens, Differentiation, T-Lymphocyte - immunology; Autoimmune diseases; Biological Sciences; Blood-Brain Barrier - immunology; Blood-Brain Barrier - pathology; Brain; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; Cell Movement - drug effects; Cell Movement - immunology; Central nervous system; Female; Humans; K562 Cells; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Lymphocyte Activation; Male; Molecules; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - immunology; Multiple Sclerosis - pathology; Natalizumab - administration & dosage; PNAS Plus; Receptors, Interleukin-2 - immunology; Receptors, Virus - immunology; T cell receptors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1524924113

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) resulting from a breakdown in peripheral immune tolerance. Although a beneficial role of natural killer (NK)-cell immune-regulatory function has been proposed, it still needs to be elucidated whether NK cells are functionally impaired as part of the disease. We observed NK cells in active MS lesions in close proximity to T cells. In accordance with a higher migratory capacity across the blood–brain barrier, CD56bright NK cells represent the major intrathecal NK-cell subset in both MS patients and healthy individuals. Investigating the peripheral blood and cerebrospinal fluid of MS patients treated with natalizumab revealed that transmigration of this subset depends on the α₄β₁ integrin very late antigen (VLA)-4. Although no MS-related changes in the migratory capacity of NK cells were observed, NK cells derived from patients with MS exhibit a reduced cytolytic activity in response to antigen-activated CD4⁺ T cells. Defective NK-mediated immune regulation in MS is mainly attributable to a CD4⁺ T-cell evasion caused by an impaired DNAX accessory molecule (DNAM)-1/CD155 interaction. Both the expression of the activating NK-cell receptor DNAM-1, a genetic alteration consistently found in MS-association studies, and up-regulation of the receptor’s ligand CD155 on CD4⁺ T cells are reduced in MS. Therapeutic immune modulation of IL-2 receptor restores impaired immune regulation in MS by increasing the proportion of CD155-expressing CD4⁺ T cells and the cytolytic activity of NK cells.