title: Unimpaired immune functions in the absence of Mrp4 (Abcc4).
abstract: Dendritic cell (DC) migration to draining lymph nodes is important for the initiation of an effective immune response. Recently we reported that the human ATP-binding cassette (ABC) transporter multidrug resistance protein 4 (MRP4 and ABCC4) is required for the migration of human DC. Since the ABC transporter MRP1 (ABCC1) was previously shown to play a role in both human and mouse DC migration, we here studied whether Mrp4 is similarly required for DC migration in mice and whether the absence of Mrp4 interferes with the generation of an immune response. Immunological responses were compared in wild-type FVB (FVBwt), FVB Mrp4 knockout (KO) or FVB Mrp4/5 double knockout (dKO) mice. Skin, a preferred immunization site, was analyzed for DC markers, as well as for Mrp1 and Mrp4 expression. Whereas Mrp1 was abundantly present within FVBwt skin, only few Mrp4 expressing cells were detected. In addition, no Mrp4 protein expression was detected on in vitro cultured FVBwt bone marrow-derived DC (BM-DC). DC migration from murine ear skin was unaltered between FVBwt and MRP4/5 dKO animals. The absence of Mrp4 also had no effect on immune responses upon allergen sensitization, immunization or oral tolerance induction. We thus conclude that in contrast to its human counterpart, murine Mrp4 is not involved in DC migration, nor indeed, in the generation of an effective immune response. These data reveal disparities in the physiological role of ABC transporters between species, which may derive from differences in substrate specificity.
authors.affiliation: Department of Pathology, VU University Medical Center/Cancer Center Amsterdam, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Rieneke
authors.initials: R
authors.lastname: van de Ven
authors.forename: Jan
authors.initials: J
authors.lastname: de Groot
authors.forename: Anneke W
authors.initials: AW
authors.lastname: Reurs
authors.forename: Pepijn G J T B
authors.initials: PG
authors.lastname: Wijnands
authors.forename: Koen
authors.initials: K
authors.lastname: van de Wetering
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: George L
authors.initials: GL
authors.lastname: Scheffer
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D012867:Skin / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010047:Ovalbumin; C489540:Abcc4 protein, mouse; C492376:Abcc5 protein, mouse; C421109:multidrug resistance-associated protein 1