title: A key role for PTP1B in dendritic cell maturation, migration, and T cell activation.
abstract: Dendritic cells (DC) are the major antigen-presenting cells bridging innate and adaptive immunity, a function they perform by converting quiescent DC to active, mature DC with the capacity to activate naïve T cells. They do this by migrating from the tissues to the T cell area of the secondary lymphoid tissues. Here, we demonstrate that myeloid cell-specific genetic deletion of PTP1B (LysM PTP1B) leads to defects in lipopolysaccharide-driven bone marrow-derived DC (BMDC) activation associated with increased levels of phosphorylated Stat3. We show that myeloid cell-specific PTP1B deletion also causes decreased migratory capacity of epidermal DC, as well as reduced CCR7 expression and chemotaxis to CCL19 by BMDC. PTP1B deficiency in BMDC also impairs their migration in vivo. Further, immature LysM PTP1B BMDC display fewer podosomes, increased levels of phosphorylated Src at tyrosine 527, and loss of Src localization to podosome puncta. In co-culture with T cells, LysM PTP1B BMDC establish fewer and shorter contacts than control BMDC. Finally, LysM PTP1B BMDC fail to present antigen to T cells as efficiently as control BMDC. These data provide first evidence for a key regulatory role for PTP1B in mediating a central DC function of initiating adaptive immune responses in response to innate immune cell activation.
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Aberdeen AB25 2ZD, UK Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK c.martin@abdn.ac.uk cm769@cam.ac.uk j.forrester@abdn.ac.uk m.delibegovic@abdn.ac.uk.
authors.forename: Cristina
authors.initials: C
authors.lastname: Martin-Granados
authors.affiliation: Division of Cell Biology and Immunology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Prescott
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Aberdeen AB25 2ZD, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Le Sommer
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Aberdeen AB25 2ZD, UK.
authors.forename: Izabela P
authors.initials: IP
authors.lastname: Klaska
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Aberdeen AB25 2ZD, UK.
authors.forename: Tian
authors.initials: T
authors.lastname: Yu
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Aberdeen AB25 2ZD, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Muckersie
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Aberdeen AB25 2ZD, UK.
authors.forename: Claudiu V
authors.initials: CV
authors.lastname: Giuraniuc
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Aberdeen AB25 2ZD, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Grant
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Aberdeen AB25 2ZD, UK c.martin@abdn.ac.uk cm769@cam.ac.uk j.forrester@abdn.ac.uk m.delibegovic@abdn.ac.uk.
authors.forename: Mirela
authors.initials: M
authors.lastname: Delibegovic
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Aberdeen AB25 2ZD, UK Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Australia Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia c.martin@abdn.ac.uk cm769@cam.ac.uk j.forrester@abdn.ac.uk m.delibegovic@abdn.ac.uk.
authors.forename: John V
authors.initials: JV
authors.lastname: Forrester
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D002454:Cell Differentiation; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D054415:Chemokine CCL19 / Q000378:metabolism; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism; D000069261:Podosomes / Q000235:genetics*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000502:physiology*; D054400:Receptors, CCR7 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D054400:Receptors, CCR7; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse
keywords: T cell activation; adaptive immune response; dendritic cell maturation; podosomes; protein tyrosine phosphatase 1B