Immunophenotypical and functional characterization of CD56bright NK cells in multiple sclerosis

Abstract

Multiple sclerosis is a T cell-mediated autoimmune disease characterized by an interplay between inflammatory and neurodegenerative processes that usually result in neurological disturbance followed by progressive accumulation of disability. In MS, regulatory T cells and CD56bright NK cell exert an immunomodulatory role. We were particularly interested in characterizing the CD56bright NK cell subset in MS because of their significant association with clinical remissions and reduced brain lesions after treatment with daclizumab.

In MS, an increase in the frequency of CD56bright after treatment with daclizumab or IFNβ-1a are known, but a phenotypical and functional characterization of this cell population has not been reported. We therefore carried out a cross-sectional analysis in healthy controls and RRMS patients, either untreated or treated with IFNβ1a, daclizumab or natalizumab. The purposes of our study were to identify patterns of NK cell surface markers expression, cytokine production and the mechanism and dynamics of CD56bright expansion.

We found that in addition to anti-CD25 mAb and IFNβ-1a, natalizumab also expands CD56bright NK cells in MS. Treatment with anti-CD25 mAb exerted the most prominent effect on the expression of NK cell markers on the CD56bright population. The expanded CD56bright cells overexpressed the surface molecules CD26, CD2, CD11b and CD6, which indicate an activated cellular pattern. The high expression of CD94 and CD62L in treated patients, indicates an intermediate state of NK cell maturation and an egress from lymph nodes to the periphery.

Our findings of similar levels of cytokine production by the CD56dim and the CD56bright cells, confront the classical definition of the CD56dim subset as only cytotoxic and the bright subset as exclusively capable to secrete cytokines. The remarkably elevated frequency of IFNγ- and TNFα-producing cells in MS without treatment, which is clearly brought to healthy donor baseline levels after treatment, supports the described pathogenic role of these cytokines in MS.

This study offers a wide phenotypical characterization of NK cells in MS that can potentially offer novel biomarkers useful for the clinical assessment of the disease as well as a potential use of NK cell-directed therapeutic approaches in autoimmune diseases such as MS.