Grant: Discovery Grants Program - Individual

) Under normal conditions bone marrow derived cells differentiate into dendritic cells (DC), monocytes and macrophages. These white blood cells are critical for innate and adaptive immunity. Monocytes and macrophages act as effectors and regulators of inflammation and innate immune responses while dendritic cells initiate and regulate antigen-specific adaptive immunity, immunologic memory and immune tolerance. We recently showed that a 14 amino acid C-terminal peptide of apolipoprotein E (ApoE), TQQIRLQAEIFQAR termed Ep1.B (239-252) induces differentiation of bone marrow derived cells and monocytes into DC-like cells and regulated immune responses in vivo (J. Immunol. 2008; 181: 6859-6871). Ep1.B induces DC-like morphology and expression of DC markers in both mouse and human cells. ApoE is a lipid transport protein with expanded function in tissue injury, cell growth and immune regulation. The mechanism by which Ep1.B induces this differentiation is the focus of this proposal and our specific aims are: a) To identify the dendritic cell subset and effector cytokines induced by Ep1.B in bone marrow derived cells and monocytes, b) To characterize the receptor for Ep1.B using the PU5-1.8 monocytic cell line, c) To functionally analyze antigen-specific CD4+ T cells in mice injected with the Ep1.B induced dendritic cell subset. ) Identification of the receptor for Ep1.B is critical to understand how innate immune signaling by Ep1.B peptide regulates differentiation of DC. These studies will provide new knowledge about dendritic cell differentiation under non-inflammatory conditions by a self-peptide that may influence innate and adaptive immunity.