Approximately 127 million pre-school age children in developing countries suffer from vitamin A deficiency, leading to increased morbidity and mortality associated with infectious disease. Studies in vitamin A deficient animals have demonstrated a marked defect in T lymphocyte-dependent antibody responses due to impaired B lymphocyte and T helper 2 lymphocyte clonal expansion. Our preliminary data supports an underlying defect in myeloid dendritic cell development in the absence of vitamin A, suggesting that the impaired B and T lymphocyte clonal expansion may result from inadequate antigen presentation. The objective of this application is to define the function of vitamin A in dendritic cell differentiation both in vitro and in vivo. We hypothesize that vitamin A is essential for the function of one or more transcription factors necessary for differentiation of dendritic cells from myeloid progenitors. We will address this hypothesis using 3 specific aims.
In Aim #1 we will determine the stage(s) in dendritic cell development in which vitamin A is required. To accomplish this aim, we will use in vitro cultures of mouse bone marrow cells stimulated with granulocyte-macrophage colony-stimulating factor to identify the myeloid progenitor that makes the dendritic cell fate choice in the presence of all-trans retinoic acid.
Aim #2 is to identify the specific molecular steps in the pathway of dendritic cell development that require vitamin A. We will address this aim by comparing transcription factor activity in nuclear protein extracts prepared from dendritic cells cultured in vitro in the presence and absence of vitamin A, using transcription factor arrays and electrophoretic mobility shift assays.
In Aim #3 we will confirm the role of vitamin A in myeloid dendritic cell hematopoiesis in vivo, by characterizing dendritic cell populations in peripheral blood, spleen, and lymph nodes of vitamin A deficient and sufficient mice. The proposed research is significant because it will lead to greater understanding of the underlying basis for increased susceptibility to infectious disease associated with vitamin A deficiency. ? ?
| Duriancik, David M; Hoag, Kathleen A (2010) Vitamin A deficiency alters splenic dendritic cell subsets and increases CD8(+)Gr-1(+) memory T lymphocytes in C57BL/6J mice. Cell Immunol 265:156-63 |
| Lackey, Denise E; Ashley, Shanna L; Davis, Alvin L et al. (2008) Retinoic acid decreases adherence of murine myeloid dendritic cells and increases production of matrix metalloproteinase-9. J Nutr 138:1512-9 |
