Natural Killer Cells Regulate Th17 Cells After Autologous Hematopoietic Stem Cell Transplantation for Relapsing Remitting Multiple Sclerosis

Abstract

In autoimmunity, the balance of different helper T (Th) cell subsets can influence the tissue damage caused by autoreactive T cells. Pro-inflammatory Th1 and Th17 T cells are implicated as mediators of several human autoimmune conditions such as multiple sclerosis (MS). Autologous hematopoietic stem cell transplantation (aHSCT) has been tested in phase 2 clinical trials for MS patients with aggressive disease. Abrogation of new clinical relapses and brain lesions can be seen after ablative aHSCT, accompanied by significant reductions in Th17, but not Th1, cell populations and activity. The cause of this selective decrease in Th17 cell responses following ablative aHSCT is not completely understood. We identified an increase in the kinetics of natural killer (NK) cell reconstitution, relative to CD4+ T cells, in MS patients post-aHSCT, resulting in an increased NK cell:CD4+ T cell ratio that correlated with the degree of decrease in Th17 responses. Ex vivo removal of NK cells from post-aHSCT peripheral blood mononuclear cells resulted in higher Th17 cell responses, indicating that NK cells can regulate Th17 activity. NK cells were also found to be cytotoxic to memory Th17 cells, and this toxicity is mediated through NKG2D-dependent necrosis. Surprisingly, NK cells induced memory T cells to secrete more IL-17A. This was preceded by an early rise in T cell expression of RORC and IL17A mRNA, and could be blocked with neutralizing antibodies against CD58, a costimulatory receptor expressed on NK cells. Thus, NK cells provide initial co-stimulation that supports the induction of a Th17 response, followed by NKG2D-dependent cytotoxicity that limits these cells. Together these data suggest that rapid reconstitution of NK cells following aHSCT contribute to the suppression of the re-emergence of Th17 cells. This highlights the importance of NK cells in shaping the reconstituting immune system following aHSCT in MS patients.

Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE)

“…Other studies examined proinflammatory T-cell effector responses specifically, including Th17 cell frequency, the mRNA expression of their master regulator ROR[gamma]t and the production of the inflammatory cytokine IL-17A all decreased post-HSCT [126]. Several additional immune mechanisms that may contribute to the efficacy of aHSCT in MS have include depletion of peripheral blood mucosal-associated invariant T (MAIT) cells, decrease of MS-associated inflammatory micro RNAs (miR-155, miR-142-3p, miR-16), along with increased immune T and NK regulatory cells and increased expression of immune checkpoint receptors and regulatory molecules such as PD-1, CTLA-4, GITR and TGF-b1 [127].…”

Enhancing natural killer cells is beneficial in multiple sclerosis – Yes

“…The same study showed that NK cells kill Th17 cells through engagement of the natural killer group 2 member D (NKG2D) receptor in healthy donors. 9 Taken together, this study and the preciously cited ones suggest the hypothesis that the enhancement of CD56 bright NK cells may represent a mechanism of action and/or a biomarker of efficacy of some treatments in MS.…”

“…Failure of regulation of T cell responses by CD56bright NK cells/whole NK cells in MS patients is associated with upregulation of an inhibitory molecule (HLA class I histocompatibility antigen, alpha chain E (HLA-E)) on T cells 5 and with decreased expression of an activated receptor, DNAX Accessory Molecule-1 (DNAM-1) on NK cells and of its ligand on T cells (CD155). 6 Second, it is notable that a number of effective treatments for MS enhances the number of CD56 bright NK cells, including interferon-beta, 11 alemtuzumab, 12 autologous hematopoietic stem cell transplantation (AHSCT), 9 and daclizumab. 13 The latter treatment was an anti-CD25 monoclonal antibody with pleiotropic effects on the IS; among such effects, the increase of CD56 bright NK cells was directly related to decreased disease activity and accompanied with enhanced cytotoxicity toward CD4+ T cells.…”

Fibroblasts as an Alternative to Mesenchymal Stem Cells with Successful Treatment and Immune Modulation in EAE Model of Multiple Sclerosis

“…It is known Treg cells are reciprocal cells to Th17 cells, and it is also known the Th17 CD4 T cell subsets plays a major role in pathology of EAE as well as numerous other autoimmune disorders in man and mice (69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79). Accordingly, we assessed the IL-17 mediated pathway in vitro and in vivo.…”