IFN-β Facilitates Neuroantigen-Dependent Induction of CD25+ FOXP3+ Regulatory T Cells That Suppress Experimental Autoimmune Encephalomyelitis.
This study introduces a flexible format for tolerogenic vaccination that incorporates IFN-β and neuroantigen (NAg) in the Alum adjuvant. Tolerogenic vaccination required all three components, IFN-β, NAg, and Alum, for inhibition of experimental autoimmune encephalomyelitis (EAE) and induction of tolerance. Vaccination with IFN-β + NAg in Alum ameliorated NAg-specific sensitization and inhibited EAE in C57BL/6 mice in pretreatment and therapeutic regimens. Tolerance induction was specific for the tolerogenic vaccine Ag PLP178-191 or myelin oligodendrocyte glycoprotein (MOG)35-55 in proteolipid protein- and MOG-induced models of EAE, respectively, and was abrogated by pretreatment with a depleting anti-CD25 mAb. IFN-β/Alum-based vaccination exhibited hallmarks of infectious tolerance, because IFN-β + OVA in Alum-specific vaccination inhibited EAE elicited by OVA + MOG in CFA but not EAE elicited by MOG in CFA. IFN-β + NAg in Alum vaccination elicited elevated numbers and percentages of FOXP3+T cells in blood and secondary lymphoid organs in 2D2 MOG-specific transgenic mice, and repeated boosters facilitated generation of activated CD44highCD25+regulatory T cell (Treg) populations. IFN-β and MOG35-55 elicited suppressive FOXP3+Tregs in vitro in the absence of Alum via a mechanism that was neutralized by anti-TGF-β and that resulted in the induction of an effector CD69+CTLA-4+IFNAR+FOXP3+Treg subset. In vitro IFN-β + MOG-induced Tregs inhibited EAE when transferred into actively challenged recipients. Unlike IFN-β + NAg in Alum vaccines, vaccination with TGF-β + MOG35-55 in Alum did not increase Treg percentages in vivo. Overall, this study indicates that IFN-β + NAg in Alum vaccination elicits NAg-specific, suppressive CD25+Tregs that inhibit CNS autoimmune disease. Thus, IFN-β has the activity spectrum that drives selective responses of suppressive FOXP3+Tregs.
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834; and.
Duncheng
0000-0002-2085-9512
D
Wang
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834; and.
Debjani
D
Ghosh
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834; and.
S M Touhidul
0000-0003-2720-4102
SM
Islam
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834; and.
Cody D
CD
Moorman
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834; and.
Ashton E
AE
Thomason
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834; and.
Daniel S
DS
Wilkinson
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834; and manniem@ecu.edu.|The Harriet and John Wooten Laboratory for Alzheimer's and Neurodegenerative Disease Research, Brody School of Medicine, East Carolina University, Greenville, NC 27834.
Mark D
0000-0003-0475-8516
MD
Mannie
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000534:Alum Compounds / Q000627:therapeutic use*; D000818:Animals; D024201:Bystander Effect; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000628:therapy*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D016899:Interferon-beta / Q000378:metabolism* / Q000627:therapeutic use; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000628:therapy*; D018991:Myelin Proteolipid Protein / Q000276:immunology / Q000627:therapeutic use*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014612:Vaccines / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D018991:Myelin Proteolipid Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D014612:Vaccines; C445081:myelin oligodendrocyte glycoprotein (35-55); C094242:myelin proteolipid protein (178-191); C041524:aluminum sulfate; D016899:Interferon-beta