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.

Tailored immunity by skin antigen-presenting cells

“…Of note, bone marrow-derived CD207 + dermal DCs also contributed to CD8 + T cell priming. 36 These findings fits nicely with the view that steady-state, non-inflammatory LCs that are used to encounter skin antigens are tolerogenic and thus enable to efficiently prime naïve CD8 + T cells, whereas LCs that are newly generated upon inflammation and entry of foreign antigen could prime naïve CD4 + and CD8 + T cells. However, a recent study on skin scarification with Vaccinia Virus showed that LCs are not involved in CD8-mediated immune responses.…”

“…35 Interestingly, after intradermal delivery of plasmid DNA, a second wave of LCs from epidermal precursors-reminiscent of long-term LCs described in 13 -was present in DLNs two weeks after immunization and was essential for CD8 + T cell priming. 36 Conversely, primary LCs residing in the epidermis at the time of vaccination could not prime CD8 + T cells. Of note, bone marrow-derived CD207 + dermal DCs also contributed to CD8 + T cell priming.…”

Specific roles for dendritic cell subsets during initiation and progression of psoriasis

“…Therefore, the differential migration capacities of LCs from psoriatic skin and the fact that only about 30% of LCs can be induced to emigrate, might reflect the existence of two types of LCs in humans. In support of this hypothesis are the observations that during inflammatory conditions, LCs can originate either from bone marrow-derived precursors or from preexisting epidermal LC precursors (Chorro et al , 2009 ; Elnekave et al , 2014 ; Ginhoux et al , 2006 ; Nagao et al , 2012 ). In DKO* mice, but not in Imi-treated mice, we found that depleted LCs were replaced from bone marrow rather than from skin-resident precursors, suggesting that two different types of LCs exist which might differently react to inflammatory conditions.…”

Dissolving Microneedle Delivery of Nanoparticle-Encapsulated Antigen Elicits Efficient Cross-Priming and Th1 Immune Responses by Murine Langerhans Cells

“…Likewise, subsequent activation of innate signaling pathways following viral or PLGA NPs internalization may differ. Interestingly, a recent study demonstrated that following plasmid DNA intradermal vaccination, CD8 þ T cell crosspriming was largely instigated by infiltrating, second generation antigen-expressing LCs (Elnekave et al, 2014). Therefore, the perceived defined functional allocations among distinct skin DC subsets may not necessarily exist, but rather the underlying mechanisms that govern antigen processing, presentation, and activation of DCs may influence their subsequent functional properties and the net immune response.…”