Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 6, Issue 12, Pages 2884-2893Publisher
BLACKWELL PUBLISHING
DOI: 10.1111/j.1600-6143.2006.01561.x
Keywords
antigen-presenting cell; CD80; dendritic cell; interleukin-12; P-glycoprotein; Th1
Categories
Funding
- NCI NIH HHS [R01 CA113796-01A1, R01 CA113796] Funding Source: Medline
- NIAID NIH HHS [K08 AI50783, K08 AI050783] Funding Source: Medline
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P-glycoprotein (P-gp) expressed on human antigen presenting cells (APC) regulates alloantigen-dependent T-cell activation, but the associated mechanisms are not well understood. Here we demonstrate that P-gp functions in IL-12-dependent monocyte differentiation into dendritic cell (DC) lineages during APC maturation, thereby regulating the capacity of myeloid-derived APCs to elicit alloimmune Th1 responses. Human CD14(+) monocytes cultured in vitro in the presence of IL-4/GM-CSF differentiated into CD14(-)CD1a(+) APCs of the immature DC phenotype. In contrast, P-gp blockade during differentiation inhibited CD1a induction, down-regulated CD80 expression, enhanced CD86 expression and induced CD68 expression. APCs differentiated in the presence of P-gp blockade stimulated alloimmune T-cell proliferation significantly less than controls and this effect was associated with 97% inhibition of Th1 IFN-gamma production, but preserved Th2 IL-5 secretion. MAb-mediated blockade of the P-gp transport substrate IL-12 in the course of APC differentiation also inhibited IFN-gamma production, while addition of rIL-12 to P-gp-blocked APC differentiation cultures significantly reversed this effect, demonstrating that P-gp functions in APC differentiation in part via IL-12 regulation. Our findings define a novel role for P-gp as a differentiation switch in APC maturation and resultant alloimmune Th1 responses, thereby identifying P-gp as a potential novel therapeutic target in allotransplantation.
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