TY - JOUR
T1 - A postmigrational switch among skin-derived dendritic cells to a macrophage-like phenotype is predetermined by the intracutaneous cytokine balance
AU - de Gruijl, Tanja D
AU - Sombroek, Claudia C
AU - Lougheed, Sinéad M
AU - Oosterhoff, Dinja
AU - Buter, Jan
AU - van den Eertwegh, Alfons J M
AU - Scheper, Rik J
AU - Pinedo, Herbert M
PY - 2006/6/15
Y1 - 2006/6/15
N2 - Migration of dendritic cells (DC) to secondary lymphoid organs under proinflammatory conditions coincides with their maturation and acquisition of T cell stimulatory abilities. In contrast, impaired activation of DC, e.g., in tumor-conditioned environments, may hamper their activation and possibly their subsequent migration to lymph nodes, leading to either immunological tolerance or ignorance, respectively. In this study, the influence of cytokines in the peripheral skin microenvironment on the activation state of migrating cutaneous DC was assessed using an ex vivo human skin explant model. We observed a phenotypic shift from mature CD83(+) DC to immature CD14(+) macrophage-like cells within 7 days subsequent to migration from unconditioned skin. These macrophage-like cells displayed a poor T cell stimulatory ability and lacked expression of CCR7, thus precluding their migration to paracortical T cell areas in the lymph nodes. The balance of suppressive and stimulatory cytokines during the initiation of migration decided the postmigrational fate of DC with IL-10 accelerating and GM-CSF and IL-4 preventing the phenotypic switch, which proved irreversible once established. These observations indicate that, in immunosuppressed environments, a postmigrational DC-to-macrophage shift may hinder T cell activation, but also that it may be prevented by prior conditioning of the tissue microenvironment by GM-CSF and/or IL-4.
AB - Migration of dendritic cells (DC) to secondary lymphoid organs under proinflammatory conditions coincides with their maturation and acquisition of T cell stimulatory abilities. In contrast, impaired activation of DC, e.g., in tumor-conditioned environments, may hamper their activation and possibly their subsequent migration to lymph nodes, leading to either immunological tolerance or ignorance, respectively. In this study, the influence of cytokines in the peripheral skin microenvironment on the activation state of migrating cutaneous DC was assessed using an ex vivo human skin explant model. We observed a phenotypic shift from mature CD83(+) DC to immature CD14(+) macrophage-like cells within 7 days subsequent to migration from unconditioned skin. These macrophage-like cells displayed a poor T cell stimulatory ability and lacked expression of CCR7, thus precluding their migration to paracortical T cell areas in the lymph nodes. The balance of suppressive and stimulatory cytokines during the initiation of migration decided the postmigrational fate of DC with IL-10 accelerating and GM-CSF and IL-4 preventing the phenotypic switch, which proved irreversible once established. These observations indicate that, in immunosuppressed environments, a postmigrational DC-to-macrophage shift may hinder T cell activation, but also that it may be prevented by prior conditioning of the tissue microenvironment by GM-CSF and/or IL-4.
KW - Biomarkers/metabolism
KW - Cell Differentiation/immunology
KW - Cell Movement/immunology
KW - Cell Proliferation
KW - Cytokines/biosynthesis
KW - Dendritic Cells/cytology
KW - Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology
KW - Humans
KW - Immunophenotyping
KW - Interleukin-4/pharmacology
KW - Langerhans Cells/immunology
KW - Lipopolysaccharide Receptors/biosynthesis
KW - Macrophages/cytology
KW - Organ Culture Techniques
KW - Skin/cytology
KW - Stem Cells/immunology
M3 - Article
C2 - 16751366
VL - 176
SP - 7232
EP - 7242
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 12
ER -