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P‐Glycoprotein Functions as a Differentiation Switch in Antigen Presenting Cell Maturation
Author(s) -
Pendse S. S.,
Behjati S.,
Schatton T.,
Izawa A.,
Sayegh M. H.,
Frank M. H.
Publication year - 2006
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2006.01561.x
Subject(s) - cd80 , cd86 , cellular differentiation , antigen presenting cell , microbiology and biotechnology , cd14 , immunology , t cell , monocyte , antigen presentation , biology , dendritic cell , antigen , cd40 , in vitro , immune system , cytotoxic t cell , biochemistry , gene
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‐γ 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‐γ 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.