Dysregulation of regulatory CD56bright 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.

Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis

“…Other groups have shown a non-sustained rise in Tregs post-AHSCT,32 and no previous study has assessed the CD39 + subset of these cells. Similarly, the immunoregulatory CD56 hi subset of NK cells19 remains high after AHSCT in patients with MS and not in patients with lymphoma suggesting an anti-inflammatory milieu in immune restoration that is specific to patients with MS post-transplant. The IR data confirm sustained changes in the immunology of patients with MS post-AHSCT which requires further elucidation with in vitro suppression assays and analysis of the cell of origin.…”

“…Immune reconstitution (IR) of patients with MS post-AHSCT suggests that transplantation removes putative proinflammatory lymphocytes such as mucosal-associated invariant T (MAIT) cells17 while regenerating immunoregulatory populations such as CD39 + T regulatory cells,18 CD56 high natural killer (NK) cells19 and suppressor CD8 + CD57 + T cells,17 some of which are recognised to be dysfunctional in MS 18. It is unclear, however, whether these changes in the immune system post-AHSCT are unique to MS or an expected consequence of the treatment itself.…”

Regulatory Functions of Natural Killer Cells in Multiple Sclerosis

“…Furthermore, IL-27-stimulated CD56 bright NK cells have been shown to suppress the proliferation of autologous CD4 + T cells in a contact-dependent manner associated with increased perforin content (9). CD56 bright NK cells, stimulated with the pro-inflammatory cytokines IL-12 and IL-15, prevent autologous CD4 + T cell proliferation through a cytotoxic mechanism involving the engagement of the natural cytotoxicity receptors (NCRs), such as NKp30 and NKp46 (24), on NK cells and the release of granzyme B (25). CD56 bright NK cells were also shown to inhibit proliferation of autologous CD4 + T cells by secreting the immunosuppressive molecule adenosine.…”

“…(C)  In the presence of the anti-IL-2Rα monoclonal antibody daclizumab, IL-2 signal through the intermediate-affinity receptor induces cytotoxicity of CD56 bright NK cells toward autologous activated CD4 + T cells (G) involving the transfer of granzyme K to target cells (23). (D) The pro-inflammatory cytokines IL-12 and IL-15 induce anti-proliferative (H) and cytotoxic function of CD56 bright NK cells toward CD4 + T cells undergoing activation through engagement of the NCRs NKp30 and NKp46 and release of granzyme B (25). (E) CD56 bright suppress proliferation of autologous CD4 + T cells (H) by releasing adenosine (26).…”

“…Given the evidence that CD56 bright NK cells are a regulatory population of the IS in healthy individuals, we have explored their function in untreated MS patients or patients with clinically isolated syndrome suggestive of MS (25). The number of CD56 bright NK cells was similar in MS patients and healthy subjects (HS).…”