Tolerogen-induced interferon-producing killer dendritic cells (IKDCs) protect against EAE.
Natural killer (NK) cells and dendritic cells (DCs) have been shown to link the innate and adaptive immune systems. Likewise, a new innate cell subset, interferon-producing killer DCs (IKDCs), shares phenotypic and functional characteristics with both DCs and NK cells. Here, we show IKDCs play an essential role in the resolution of experimental autoimmune encephalomyelitis (EAE) upon treatment with the tolerizing agent, myelin oligodendrocyte glycoprotein (MOG), genetically fused to reovirus protein σ1 (termed MOG-pσ1). Activated IKDCs were recruited subsequent MOG-pσ1 treatment of EAE, and disease resolution was abated upon NK1.1 cell depletion. These IKDCs were able to kill activated CD4(+) T cells and mature dendritic DCs, thus, contributing to EAE remission. In addition, IKDCs were responsible for MOG-pσ1-mediated MOG-specific regulatory T cell recruitment to the CNS. The IKDCs induced by MOG-pσ1 expressed elevated levels of HVEM for interactions with cognate ligand-positive cells: LIGHT(+) NK and T(eff) cells and BTLA(+) B cells. Further characterization revealed these activated IKDCs being MHC class II(high), and upon their adoptive transfer (CD11c(+)NK1.1(+)MHC class II(high)), IKDCs, but not CD11c(+)NK1.1(+)MHC class II(intermediate/low) (unactivated) cells, conferred protection against EAE. These activated IKDCs showed enhanced CD107a, PD-L1, and granzyme B expression and could present OVA, unlike unactivated IKDCs. Thus, these results demonstrate the interventional potency induced HVEM(+) IKDCs to resolve autoimmune disease.
Department of Immunology and Infectious Diseases, Montana State University, 960 Technology Blvd., Bozeman, MT 59718, USA.
Eduardo
E
Huarte
Agnieszka
A
Rynda-Apple
Carol
C
Riccardi
Jerod A
JA
Skyberg
Sarah
S
Golden
Maryclare F
MF
Rollins
Andrew G
AG
Ramstead
Larissa O
LO
Jackiw
Massimo
M
Maddaloni
David W
DW
Pascual
D019264:Adoptive Transfer; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D007108:Immune Tolerance; D007372:Interferons / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D009185:Myelin Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D063308:Myelin-Oligodendrocyte Glycoprotein; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012008:Recurrence; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000950:Antigens, Ly; C527211:Klrb1c protein, mouse; C571327:Mog protein, mouse; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D055651:NK Cell Lectin-Like Receptor Subfamily B; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; C571072:myelin oligodendrocyte glycoprotein-reovirus type 3 protein sigma 1 fusion protein; D007372:Interferons