Role of fatty-acid synthesis in dendritic cell generation and function

Dendritic cells (DC) are professional APCs that regulate innate and adaptive immunity. The role of fatty-acid synthesis in DC development and function is uncertain. We found that blockade of fatty-acid synthesis markedly decreases dendropoiesis in the liver and in primary and secondary lymphoid orga...

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Published in:The Journal of immunology (1950) 2013-05, Vol.190 (9), p.4640-4649
Main Authors: Rehman, Adeel, Hemmert, Keith C, Ochi, Atsuo, Jamal, Mohsin, Henning, Justin R, Barilla, Rocky, Quesada, Juan P, Zambirinis, Constantinos P, Tang, Kerry, Ego-Osuala, Melvin, Rao, Raghavendra S, Greco, Stephanie, Deutsch, Michael, Narayan, Suchithra, Pachter, H Leon, Graffeo, Christopher S, Acehan, Devrim, Miller, George
Format: Article
Language:English
Subjects:
Animals
Apoptosis - immunology
B7-1 Antigen - immunology
B7-1 Antigen - metabolism
B7-2 Antigen - immunology
B7-2 Antigen - metabolism
bcl-X Protein - immunology
bcl-X Protein - metabolism
Caspase 3 - immunology
Caspase 3 - metabolism
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - metabolism
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - metabolism
Cell Differentiation - immunology
Chemokine CCL2 - immunology
Chemokine CCL2 - metabolism
Cyclin B1 - immunology
Cyclin B1 - metabolism
Dendritic Cells - cytology
Dendritic Cells - immunology
Dendritic Cells - metabolism
Endoplasmic Reticulum - immunology
Endoplasmic Reticulum - metabolism
Fatty Acids - biosynthesis
Fatty Acids - immunology
Fatty Acids - metabolism
Genes, MHC Class II - immunology
Humans
Intercellular Adhesion Molecule-1 - immunology
Intercellular Adhesion Molecule-1 - metabolism
Interferon-gamma - immunology
Interferon-gamma - metabolism
Interleukin-12 - immunology
Interleukin-12 - metabolism
Killer Cells, Natural - immunology
Killer Cells, Natural - metabolism
Leukocytes, Mononuclear - immunology
Leukocytes, Mononuclear - metabolism
Liver - immunology
Liver - metabolism
Male
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase Kinases - immunology
Mitogen-Activated Protein Kinase Kinases - metabolism
PPAR gamma - immunology
PPAR gamma - metabolism
Proto-Oncogene Proteins c-akt - immunology
Proto-Oncogene Proteins c-akt - metabolism
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Cytotoxic - metabolism
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Summary:Dendritic cells (DC) are professional APCs that regulate innate and adaptive immunity. The role of fatty-acid synthesis in DC development and function is uncertain. We found that blockade of fatty-acid synthesis markedly decreases dendropoiesis in the liver and in primary and secondary lymphoid organs in mice. Human DC development from PBMC precursors was also diminished by blockade of fatty-acid synthesis. This was associated with higher rates of apoptosis in precursor cells and increased expression of cleaved caspase-3 and BCL-xL and downregulation of cyclin B1. Further, blockade of fatty-acid synthesis decreased DC expression of MHC class II, ICAM-1, B7-1, and B7-2 but increased their production of selected proinflammatory cytokines including IL-12 and MCP-1. Accordingly, inhibition of fatty-acid synthesis enhanced DC capacity to activate allogeneic as well as Ag-restricted CD4(+) and CD8(+) T cells and induce CTL responses. Further, blockade of fatty-acid synthesis increased DC expression of Notch ligands and enhanced their ability to activate NK cell immune phenotype and IFN-γ production. Because endoplasmic reticulum (ER) stress can augment the immunogenic function of APC, we postulated that this may account for the higher DC immunogenicity. We found that inhibition of fatty-acid synthesis resulted in elevated expression of numerous markers of ER stress in humans and mice and was associated with increased MAPK and Akt signaling. Further, lowering ER stress by 4-phenylbutyrate mitigated the enhanced immune stimulation associated with fatty-acid synthesis blockade. Our findings elucidate the role of fatty-acid synthesis in DC development and function and have implications to the design of DC vaccines for immunotherapy.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1202312