PT - JOURNAL ARTICLE AU - Belinda Carrión AU - Yawei Liu AU - Mahdieh Hadi AU - Jon Lundstrom AU - Jeppe Romme Christensen AU - Cecilie Ammitzbøll AU - Morten Hanefeld Dziegiel AU - Per Soelberg Sørensen AU - Manuel Comabella AU - Xavier Montalban AU - Finn Sellebjerg AU - Shohreh Issazadeh-Navikas TI - Transcriptome and Function of Novel Immunosuppressive Autoreactive Invariant Natural Killer T Cells That Are Absent in Progressive Multiple Sclerosis AID - 10.1212/NXI.0000000000001065 DP - 2021 Nov 01 TA - Neurology - Neuroimmunology Neuroinflammation PG - e1065 VI - 8 IP - 6 4099 - http://nn.neurology.org/content/8/6/e1065.short 4100 - http://nn.neurology.org/content/8/6/e1065.full SO - Neurol Neuroimmunol Neuroinflamm2021 Nov 01; 8 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