iC3b arrests monocytic cell differentiation into CD1c-expressing dendritic cell precursors: a mechanism for transiently decreased dendritic cells in vivo after human skin injury by ultraviolet B.
Our previous data indicated that C3, its bioactive product iC3b, and the iC3b ligand CD11b are critical for ultraviolet-induced immunosuppression. We thus hypothesized that iC3b is an important skin-based factor regulating CD11b+ monocytic cell function in the acute post-ultraviolet period. Although monocytic cell migration peaked at 1-3 d after ultraviolet exposure of skin, dermal CD1c dendritic cells underwent a rapid and prolonged depletion that did not recover until day 7. Because ultraviolet-induced iC3b deposits are reciprocally maximal on day 3, but fade by day 7, we next hypothesized that iC3b can be responsible for the delay in differentiation into dendritic cells of monocytic cells migrating into ultraviolet-exposed skin. Analysis of dermal cells derived from keratome biopsies suggested that iC3b exposure could inhibit the development of CD1c+ dermal cells. To model newly immigrating blood monocytes entering ultraviolet-exposed, iC3b-containing dermis, purified monocytes from human blood were induced with granulocyte-macrophage colony stimulating factor to generate a population of dendritic cell precursors expressing CD1c. Incubation with iC3b markedly inhibited the appearance of CD1c+ cells (p<0.05) and induced CD1c-CD14+ cells. This inhibition was reversed by coincubation with an anti-CD11b antibody that blocks the iC3b binding site. Other functions associated with dendritic cell maturation were also inhibited by iC3b, such as interleukin-12p70 production as well as CD80 and CD40 expression. Restimulation of monocytes for DC maturation revealed that iC3b induced a temporary inhibition of DC differentiation. Thus, a human skin response in which iC3b is transiently (3-7 d) generated in dermis, such as ultraviolet, can arrest monocytic skin-infiltrating cells from undergoing dendritic cell precursor differentiation.
Takahara
Masakazu
M
Department of Dermatology, and Research Institute of University Hospitals of Cleveland, and Case Western Reserve University, Cleveland, Ohio 44106, USA.
Kang
Kefei
K
Liu
Liming
L
Yoshida
Yuichi
Y
McCormick
Thomas S
TS
Cooper
Kevin D
KD
D000818:Animals; D018949:Antigens, CD1 / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000096:biosynthesis; D019013:CD40 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation; D003179:Complement C3b / Q000378:metabolism / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006023:Glycoproteins / Q000096:biosynthesis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D012756:Sheep; D013997:Time Factors; D014466:Ultraviolet Rays; D015854:Up-Regulation
D018949:Antigens, CD1; D018122:B7-1 Antigen; C437944:CD1C protein, human; D019013:CD40 Antigens; D016207:Cytokines; D006023:Glycoproteins; D006684:HLA-DR Antigens; D007075:Immunoglobulin M; D018950:Lipopolysaccharide Receptors; D018664:Interleukin-12; D015847:Interleukin-4; D003179:Complement C3b; D016178:Granulocyte-Macrophage Colony-Stimulating Factor