title: PD-1 on immature and PD-1 ligands on migratory human Langerhans cells regulate antigen-presenting cell activity.
abstract: Langerhans cells (LCs) are known as "sentinels" of the immune system that function as professional antigen-presenting cells (APCs) after migration to draining lymph node. LCs are proposed to have a role in tolerance and the resolution of cutaneous immune responses. The Programmed Death-1 (PD-1) receptor and its ligands, PD-L1 and PD-L2, are a co-inhibitory pathway that contributes to the negative regulation of T-lymphocyte activation and peripheral tolerance. Surprisingly, we found PD-1 to be expressed on immature LCs (iLCs) in situ. PD-1 engagement on iLCs reduced IL-6 and macrophage inflammatory protein (MIP)-1alpha cytokine production in response to TLR2 signals but had no effect on LC maturation. PD-L1 and PD-L2 were expressed at very low levels on iLCs. Maturation of LCs upon migration from epidermis led to loss of PD-l expression and gain of high expression of PD-L1 and PD-L2 as well as co-stimulatory molecules. Blockade of PD-L1 and/or PD-L2 on migratory LCs (mLCs) and DDCs enhanced T-cell activation, as has been reported for other APCs. Thus the PD-1 pathway is active in iLCs and inhibits iLC activities, but expression of receptor and ligands reverses upon maturation and PD-L1 and PD-L2 on mLC function to inhibit T-cell responses.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Peña-Cruz
authors.forename: Sean M
authors.initials: SM
authors.lastname: McDonough
authors.forename: Felipe
authors.initials: F
authors.lastname: Diaz-Griffero
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Crum
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Carrasco
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D015703:Antigens, CD / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D060890:B7-H1 Antigen; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D016130:Immunophenotyping; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D019169:Jurkat Cells; D007801:Langerhans Cells / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; D016207:Cytokines; D007136:Immunoglobulins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D051195:Toll-Like Receptor 2; D000097802:CD83 Antigen; C423236:CD274 protein, human; C497964:CD86 protein, human; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; C495342:TLR2 protein, human
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