title: Second-generation Langerhans cells originating from epidermal precursors are essential for CD8+ T cell priming.
abstract: In vivo studies questioned the ability of Langerhans cells (LCs) to mediate CD8(+) T cell priming. To address this issue, we used intradermal immunization with plasmid DNA, a system in which activation of CD8(+) T cells depends on delayed kinetics of Ag presentation. We found that dendritic cells (DCs) located in the skin at the time of immunization have limited ability to activate CD8(+) T cells. This activity was mediated by a second generation of DCs that differentiated in the skin several days after immunization, as well as by lymph node-resident DCs. Intriguingly, CD8(+) T cell responses were not affected following treatment with clodronate liposomes, immunization of CCR2(-/-) mice, or local neutralization of CCL20. This suggests that local, rather than blood-derived, DC precursors mediate CD8(+) T cell priming. Analysis of DC differentiation in the immunized skin revealed a gradual increase in the number of CD11c(+) cells, which reached their maximum 2 wk after immunization. A similar differentiation kinetics was observed for LCs, with the majority of differentiating LCs proliferating in situ from epidermal precursors. By using B6/Langerin-diphtheria toxin receptor chimeric mice and LC ablation, we demonstrated that epidermal LCs were crucial for the elicitation of CD8(+) T cell responses in vivo. Furthermore, LCs isolated from lymph nodes 2 wk after immunization contained the immunization plasmid and directly activated Ag-specific CD8(+) T cells ex vivo. Thus, these results indicate that second-generation Ag-expressing LCs differentiating from epidermal precursors directly prime CD8(+) T cells and are essential for optimal cellular immune responses following immunization with plasmid DNA.
authors.affiliation: Institute of Dental Sciences, Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel.
authors.forename: Mazal
authors.initials: M
authors.lastname: Elnekave
authors.forename: Karina
authors.initials: K
authors.lastname: Furmanov
authors.forename: Yaffa
authors.initials: Y
authors.lastname: Shaul
authors.forename: Tal
authors.initials: T
authors.lastname: Capucha
authors.forename: Luba
authors.initials: L
authors.lastname: Eli-Berchoer
authors.forename: Katya
authors.initials: K
authors.lastname: Zelentsova
authors.forename: Björn E
authors.initials: BE
authors.lastname: Clausen
authors.forename: Avi-Hai
authors.initials: AH
authors.lastname: Hovav
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D054418:Chemokine CCL20 / Q000276:immunology; D004002:Clodronic Acid; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D015744:Giant Cells, Langhans / Q000276:immunology*; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010957:Plasmids / Q000235:genetics; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D012867:Skin / Q000166:cytology / Q000276:immunology
chemical_list: C493447:CCL20 protein, mouse; D039521:CD11c Antigen; C515335:Ccr2 protein, mouse; D054418:Chemokine CCL20; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D054390:Receptors, CCR2; D004002:Clodronic Acid