Transcriptome and Function of Novel Immunosuppressive Autoreactive Invariant Natural Killer T Cells That Are Absent in Progressive Multiple Sclerosis

Belinda Carrión, Yawei Liu, Mahdieh Hadi, Jon Lundstrom, Jeppe Romme Christensen, Cecilie Ammitzbøll, Morten Hanefeld Dziegiel, Per Soelberg Sørensen, Manuel Comabella, Xavier Montalban, Finn Sellebjerg, Shohreh Issazadeh-Navikas

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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.

Original languageEnglish
Number of pages14
JournalNeurology: Neuroimmunology and NeuroInflammation
Issue number6
Publication statusPublished - 1 Nov 2021


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