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* Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada;
Robarts Research Institute, London, Ontario, Canada;
Department of Immunobiology, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, CT 06520; and
Institute of Infection and Immunity, Canadian Institutes of Health Research, London, Ontario, Canada
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-
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-
B, 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Canadian Institutes of Health Research. J.M. is a Tier 1 Canada Research Chair in Immunobiology. R.A.F. is an investigator of the Howard Hughes Medical Institute.
2 T.A.S. and E.N. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Bhagirath Singh, Department of Microbiology and Immunology, Dental Science Building, University of Western Ontario, London, Ontario N6A 5C1, Canada. E-mail address: bsingh{at}uwo.ca
4 Abbreviations used in this paper: DC, dendritic cell; ApoE, apolipoprotein E; BMDC, bone marrow-derived DC; NAC, N-acetyl-L-cysteine; PVDF, polyvinylidene difluoride.
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