Table 1 MS therapies and their effect on CD56^bright NK cells

Daclizumab

Monoclonal antibody against the α-chain of IL-2Rα. Inhibits effector T-cell activation, regulatory T-cell expansion and activation-induced T-cell apoptosis

Increases CD56^bright NK cell numbers via IL-2Rβ intracellular signaling

Increases CD56^bright NK cells in the CSF

[5, 61, 100, 123]

Natalizumab

Monoclonal antibody against α4-integrin of VLA-4. Blocks the binding of immune cells to endothelial cells and prevents immune cell migration towards the CNS

Increases total NK cell numbers. Decrease frequency CD56^bright NK cells

Blocks trafficking of NK cells. Decreases numbers of NK cells in the CNS and lymph nodes

[159,160,161]

Interferon-β

Immunomodulatory properties. Inhibits T-cell proliferation and impairs trafficking of immune cells into the CNS

Expands CD56^bright NK cells and even higher expansion on responders. Alters the phenotype with decreased expression of the inhibitory receptor LILRB1 and increased expression of NKG2A receptor

NA

[162,163,164,165]

Glatiramer acetate

Resembles myelin basic protein and binds to MHCII in antigen-presenting cells, competing with other antigens and limiting the presentation of self-antigens

No differences of CD56^bright NK cell frequencies. Enhances killing of autologous immature and mature dendritic cells in vitro and in MS patients. Increases expression of activating NKG2D and NKp46 receptors

No differences in NK cell numbers nor CD69 expression

[166,167,168,169,170]

Fingolimod

Agonist of sphingosine 1-phosphate receptor, which inhibits lymphocyte egress from lymph nodes, preventing the migration of autoreactive T cells into the CNS

Decreases CD56^bright NK cell numbers, and even higher decrease in non-responders. No effects on cytokine production of IFN-γ, TNF and IL-10, nor in HLA-DR expression on NK cells. Increases migration in vitro towards CXCL12, but decreased towards CX3CL1. Blocks the egress of immature NK cells from the lymph nodes

NA

[160, 171,172,173,174]

Dimethyl fumarate

Fumaric acid ester that activates the nuclear factor-kβ pathway and the neuroprotective nuclear factor (erythroid-derived 2)-related factor 2, which regulates inflammation and protects neural cells

Increases the number of CD56^bright NK cells. This increase correlated negatively with the numbers of CD8⁺ T cells producing IFN-γ and TNF. Increases numbers of CD107a⁺ cells, as a measure of increased degranulation

NA

[175,176,177]

Ocrelizumab

Humanized monoclonal antibody that targets CD20⁺ cells

Discrete decrease of CD56^bright NK cells

NA

[178]

Cladribine

Synthetic chlorinated deoxyadenosine analogue. Cladribine phosphates accumulate in proliferative cells interfering with DNA synthesis and repair, which leads to cell death. The main effects are in lymphocytes

No effects on CD56^bright NK cell numbers

NA

[14, 179]