Dendritic cell populations with different concentrations of lipid regulate tolerance and immunity in mouse and human liver.
OBJECTIVE
Immune cells of the liver must be able to recognize and react to pathogens yet remain tolerant to food molecules and other nonpathogens. Dendritic cells (DCs) are believed to contribute to hepatic tolerance. Lipids have been implicated in dysfunction of DCs in cancer. Therefore, we investigated whether high lipid content in liver DCs affects induction of tolerance.


METHODS
Mouse and human hepatic nonparenchymal cells were isolated by mechanical and enzymatic digestion. DCs were purified by fluorescence-activated cell sorting or with immunomagnetic beads. DC lipid content was assessed by flow cytometry, immune fluorescence, and electron microscopy and by measuring intracellular component lipids. DC activation was determined from surface phenotype and cytokine profile. DC function was assessed in T-cell, natural killer (NK) cell, and NKT cell coculture assays as well as in vivo.


RESULTS
We observed 2 distinct populations of hepatic DCs in mice and humans based on their lipid content and expression of markers associated with adipogenesis and lipid metabolism. This lipid-based dichotomy in DCs was unique to the liver and specific to DCs compared with other hepatic immune cells. However, rather than mediate tolerance, the liver DC population with high concentrations of lipid was immunogenic in multiple models; they activated T cells, NK cells, and NKT cells. Conversely, liver DCs with low levels of lipid induced regulatory T cells, anergy to cancer, and oral tolerance. The immunogenicity of lipid-rich liver DCs required their secretion of tumor necrosis factor α and was directly related to their high lipid content; blocking DC synthesis of fatty acids or inhibiting adipogenesis (by reducing endoplasmic reticular stress) reduced DC immunogenicity.


CONCLUSIONS
Human and mouse hepatic DCs are composed of distinct populations that contain different concentrations of lipid, which regulates immunogenic versus tolerogenic responses in the liver.
S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York 10016, USA.
Junaid
J
Ibrahim
Andrew H
AH
Nguyen
Adeel
A
Rehman
Atsuo
A
Ochi
Mohsin
M
Jamal
Christopher S
CS
Graffeo
Justin R
JR
Henning
Constantinos P
CP
Zambirinis
Nina C
NC
Fallon
Rocky
R
Barilla
Sana
S
Badar
Aaron
A
Mitchell
Raghavendra S
RS
Rao
Devrim
D
Acehan
Alan B
AB
Frey
George
G
Miller
D050156:Adipogenesis; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D055610:Antigens, CD1d / Q000378:metabolism; D017209:Apoptosis; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis*; D008099:Liver / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D055611:Natural Killer T-Cells / Q000502:physiology; D010641:Phenotype; D013601:T-Lymphocytes / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015703:Antigens, CD; D055610:Antigens, CD1d; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D039481:CD11b Antigen; D019013:CD40 Antigens; D008055:Lipids; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D017493:Leukocyte Common Antigens