title: Dendritic cell differentiation induced by a self-peptide derived from apolipoprotein E.
abstract: Dendritic cells (DCs) are professional APCs and potent stimulators of naive T cells. Since DCs have the ability to immunize or tolerize T cells they are unique candidates for use in immunotherapy. Our laboratory has discovered that a naturally processed self-peptide from apolipoprotein E, Ep1.B, induces DC-like morphology and surface marker expression in a murine monocytic cell line (PU5-1.8), human monocytic cell line (U937), murine splenocytes, and human peripheral blood monocytes. Microscopy and flow cytometric analysis revealed that Ep1.B-treated cells display decreased adherence to plastic and increased aggregation, dendritic processes, and expression of DC surface markers, including DEC-205, CD11c, B7.1, and B7.2. These effects were observed in both PU5-1.8 cells and splenocytes from various mouse strains including BALB/c, C57BL/6, NOD/Lt, and C3H/HeJ. Coadministration of Ep1.B with OVA antigenic peptide functions in dampening specific immune response to OVA. Ep1.B down-regulates proliferation of T cells and IFN-gamma production and stimulates IL-10 secretion in immunized mice. Ep1.B-induced differentiation resulted in the activation of PI3K and MAPK signaling pathways, including ERK1/2, p38, and JNK. We also found that NF-kappaB, a transcription factor essential for DC differentiation, is critical in mediating the effects of Ep1.B. Ep1.B-induced differentiation is independent of MyD88-dependent pathway of TLR signaling. Cumulatively, these findings suggest that Ep1.B acts by initiating a signal transduction cascade in monocytes leading to their differentiation into DCs.
authors.affiliation: Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Stephens
authors.forename: Enayat
authors.initials: E
authors.lastname: Nikoopour
authors.forename: Beverly J
authors.initials: BJ
authors.lastname: Rider
authors.forename: Matilde
authors.initials: M
authors.lastname: Leon-Ponte
authors.forename: Thu A
authors.initials: TA
authors.lastname: Chau
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mikolajczak
authors.forename: Pratibha
authors.initials: P
authors.lastname: Chaturvedi
authors.forename: Edwin
authors.initials: E
authors.lastname: Lee-Chan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: S M Mansour
authors.initials: SM
authors.lastname: Haeryfar
authors.forename: Joaquin
authors.initials: J
authors.lastname: Madrenas
authors.forename: Bhagirath
authors.initials: B
authors.lastname: Singh
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000276:immunology*; D015153:Blotting, Western; D002448:Cell Adhesion / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D010446:Peptide Fragments / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001057:Apolipoproteins E; D010446:Peptide Fragments; C524718:apolipoprotein E (239-252), mouse