Abstract
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.
Glossary
- 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
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
The Article Procesing Charge was funded by Lundbeck Foundation; Danish Multiple Sclerosis Society, Independent Research Fund Denmark-Medical and Health Sciences (DFF-M), and Foundation for Research in Neurology to SI-N. Belinda Carrion received a PhD fellowship from CONACYT-Mexico and the Lundbeck.
- Received February 4, 2021.
- Accepted in final form June 16, 2021.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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