RT Journal Article
SR Electronic
T1 Transcriptome and Function of Novel Immunosuppressive Autoreactive Invariant Natural Killer T Cells That Are Absent in Progressive Multiple Sclerosis
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e1065
DO 10.1212/NXI.0000000000001065
VO 8
IS 6
A1 Belinda Carrión
A1 Yawei Liu
A1 Mahdieh Hadi
A1 Jon Lundstrom
A1 Jeppe Romme Christensen
A1 Cecilie Ammitzbøll
A1 Morten Hanefeld Dziegiel
A1 Per Soelberg Sørensen
A1 Manuel Comabella
A1 Xavier Montalban
A1 Finn Sellebjerg
A1 Shohreh Issazadeh-Navikas
YR 2021
UL http://nn.neurology.org/content/8/6/e1065.abstract
AB Background and Objective The aim of this study was to determine whether natural killer T (NKT) cells, including invariant (i) NKT cells, have clinical value in preventing the progression of multiple sclerosis (MS) by examining the mechanisms by which a distinct self-peptide induces a novel, protective invariant natural killer T cell (iNKT cell) subset.Methods We performed a transcriptomic and functional analysis of iNKT cells that were reactive to a human collagen type II self-peptide, hCII707-721, measuring differentially induced genes, cytokines, and suppressive capacity.Results We report the first transcriptomic profile of human conventional vs novel hCII707-721–reactive iNKT cells. We determined that hCII707-721 induces protective iNKT cells that are found in the blood of healthy individuals but not progressive patients with MS (PMS). By transcriptomic analysis, we observed that hCII707-721 promotes their development and proliferation, favoring the splicing of full-length AKT serine/threonine kinase 1 (AKT1) and effector function of this unique lineage by upregulating tumor necrosis factor (TNF)-related genes. Furthermore, hCII707-721–reactive iNKT cells did not upregulate interferon (IFN)-γ, interleukin (IL)-4, IL-10, IL-13, or IL-17 by RNA-seq or at the protein level, unlike the response to the glycolipid alpha-galactosylceramide. hCII707-721–reactive iNKT cells increased TNFα only at the protein level and suppressed autologous-activated T cells through FAS-FAS ligand (FAS-FASL) and TNFα-TNF receptor I signaling but not TNF receptor II.Discussion Based on their immunomodulatory properties, NKT cells have a potential value in the treatment of autoimmune diseases, such as MS. These significant findings suggest that endogenous peptide ligands can be used to expand iNKT cells, without causing a cytokine storm, constituting a potential immunotherapy for autoimmune conditions, including PMS.AKT1=AKT serine/threonine kinase 1; cDMEM=complete Dulbecco's Modified Eagle Medium; CFSE=carboxyfluorescein succinimidyl ester; convT=conventional CD4+ T cells; DMEM=Dulbecco's Modified Eagle Medium; DN=double-negative; EAE=experimental autoimmune encephalomyelitis; FACS=fluorescence-activated cell sorting; FAS-FASL=FAS-FAS ligand; FDR=false discovery rate; GSEA=gene set enrichment analysis; HC=healthy control; HD=healthy donor; IFN=interferon; IL=interleukin; iNKT cell=invariant natural killer T cell; MS=multiple sclerosis; NKT=natural killer T cell; PMS=progressive MS, including PPMS and SPMS; PBMC=peripheral blood mononuclear cell; PPMS=primary progressive MS; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS; TNF=tumor necrosis factor; TNFRI=TNF receptor I; TNFRII=TNF receptor II; α-Galcer=alpha-galactosylceramide; 7AAD=7-aminoactinomycin D