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

Abstract

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, CD56

Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages

“…Further experiments confirmed that these changes resulted mainly from the up-regulation of ChAT expression in CD56 bright subsets of NK cells (Fig. S5 D-F), which were reported to be activated under MS conditions rather than the CD56 dim CD16 bright NK cells (15). Unlike murine NK cells, human NK subsets did not show a simple increase in ChAT expression along with their maturation from CD56 bright to CD16 bright NK cells in normal conditions; an up-regulation in CD56 bright subsets was found only in MS patients.…”

“…The expression and up-regulation of the nonneural cholinergic system are fine-tuned via chemical or neural stimulation as a mechanism to regulate or counteract the immune system (44, NK cells develop functionally as they circulate through various organs after migrating from the bone marrow (46)(47)(48)(49). Here, ChAT-eGFP expression was observed mostly in NK cell subsets of a mature phenotype in the periphery and was enhanced after EAE induction, which may correspond to the finding that more NK cells are mobilized under inflammatory conditions, possibly facilitating their maturation or activation (15,50). However, the percentage of NK cells with ChAT expression did not seem to show a simple positive relationship with the severity of disease in certain organs.…”

“…The CD56 bright subset of human NK cells was shown to provide immune protection under MS conditions, the effect of which was proven and amplified by daclizumab or daclizumab high-yield process treatment (11)(12)(13)(14)(15)(16). CNS-resident NK cells mediate immune suppression during the acute stage of CNS autoimmune diseases via cross-talk with microglia/macrophages of the CNS (17,18).…”

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

“…The involvement of B-lymphocytes in the pathogenesis of MS is better understood: they produce autoantibodies; induce, maintain, and reactivate CD4 + T-cells; act as antigen-presenting cells; and produce pro-inflammatory cytokines (7). Impairment in the immunoregulatory function of NK cells in MS patients has also been decribed (12). A schematic overview of the roles of immune cells in MS pathogenesis is represented in Figure 1.…”

Pharmacodynamic effects of daclizumab in the intrathecal compartment

“…This observation prompted a hypothesis that subclinical MS disease activity may be mediated by residual inflammation compartmentalized to the central nervous system (CNS) and therefore mostly inaccessible to current DMTs. To test this hypothesis, we investigated a group of patients with sustained clinical response to daclizumab (Zinbryta), a humanized monoclonal antibody that selectively binds to the high‐affinity interleukin‐2 (IL‐2) receptor subunit (CD25),5, 6, 7 and has been recently approved for the treatment of relapsing forms of MS.…”