Laser‐assisted epicutaneous immunization to target human skin dendritic cells

Tripp, Christoph H.; Voit, Hermann; An, Angela; Seidl‐Philipp, Magdalena; Krapf, Johanna; Sigl, Stephan; Romani, Nikolaus; Frari, Barbara Del; Stoitzner, Patrizia

doi:10.1111/exd.14346

Cited by 7 publications

(6 citation statements)

References 57 publications

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“…The human skin explant model is a suitable tool to study antigen delivery to skin DC in their natural environment, which is of immense interest for translating knowledge into the clinics [ 27 , 34 , 35 ]. This model allows to investigate human skin DC function in a vaccination setting as close as possible to the in vivo situation.…”

Section: Resultsmentioning

confidence: 99%

Targeted delivery of a vaccine protein to Langerhans cells in the human skin via the C‐type lectin receptor Langerin

et al. 2022

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Human skin is a preferred vaccination site as it harbors multiple dendritic cell (DC) subsets, which display distinct C-type lectin receptors (CLR) that recognize pathogens. Antigens can be delivered to CLR by antibodies or ligands to boost antigen-specific immune responses. This concept has been established in mouse models but detailed insights into the functional consequences of antigen delivery to human skin DC in situ are sparse. In this study, we cloned and produced an anti-human Langerin antibody conjugated to the EBV nuclear antigen 1 (EBNA1). We confirmed specific binding of anti-Langerin-EBNA1 to Langerhans cells (LC). This novel LC-based vaccine was then compared to an existing anti-DEC-205-EBNA1 fusion protein by loading LC in epidermal cell suspensions before coculturing them with autologous T cells. After restimulation with EBNA1-peptides, we detected elevated levels of IFN-and TNF--positive CD4+ T cells with both vaccines. When we injected the fusion proteins intradermally into human skin explants, emigrated skin DC targeted via DEC-205-induced cytokine production by T cells, whereas the Langerin-based vaccine failed to do so. In summary, we demonstrate that antibodytargeting approaches via the skin are promising vaccination strategies, however, further optimizations of vaccines are required to induce potent immune responses.

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Section: Resultsmentioning

confidence: 99%

Targeted delivery of a vaccine protein to Langerhans cells in the human skin via the C‐type lectin receptor Langerin

et al. 2022

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“…We showed that local attenuation of RTN1A functionality with an N-terminus-targeting ab caused significant changes in the morphology of rLCs, leading to a roundish cell body with reduced dendrite length and dendrite distribution. Labelling of rLCs in human skin ex vivo 58 and in mouse skin in vivo 59 has been successfully employed before, yet in this study we targeted an intracellular protein. These observations led us to conclude that RTN1A is promoting elongation of dendrites in rLCs.…”

Section: Discussionmentioning

confidence: 99%

Interoperability of RTN1A in dendrite dynamics and immune functions in human Langerhans cells

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Pfisterer

Leitner

et al. 2022

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Skin is an active immune organ where professional antigen-presenting cells such as epidermal Langerhans cells (LCs) link innate and adaptive immune responses. While Reticulon 1A (RTN1A) was recently identified in LCs and dendritic cells in cutaneous and lymphoid tissues of humans and mice, its function is still unclear. Here, we studied the involvement of this protein in cytoskeletal remodeling and immune responses towards pathogens by stimulation of Toll-like receptors (TLRs) in resident LCs (rLCs) and emigrated LCs (eLCs) in human epidermis ex vivo and in a transgenic THP-1 RTN1A+ cell line. Hampering RTN1A functionality through an inhibitory antibody induced significant dendrite retraction of rLCs and inhibited their emigration. Similarly, expression of RTN1A in THP-1 cells significantly altered their morphology, enhanced aggregation potential, and inhibited the Ca2+ flux. Differentiated THP-1 RTN1A+ macrophages exhibited long cell protrusions and a larger cell body size in comparison to wild type cells. Further, stimulation of epidermal sheets with bacterial lipoproteins (TLR1/2 and TLR2) and single-stranded RNA (TLR7) resulted in the formation of substantial clusters of rLCs and a significant decrease of RTN1A expression in eLCs. Together, our data indicate involvement of RTN1A in dendrite dynamics and structural plasticity of primary LCs. Moreover, we discovered a relation between activation of TLRs, clustering of LCs, and downregulation of RTN1A within the epidermis, thus indicating an important role of RTN1A in LC residency and maintaining tissue homeostasis.

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“…We showed that local attenuation of RTN1A functionality with an N-terminus-targeting ab caused significant changes in the morphology of rLCs, leading to a roundish cell body with reduced dendrite length and dendrite distribution. Labeling of rLCs in human skin ex vivo ( Tripp et al, 2021 ) and in mouse skin in vivo ( Flacher et al, 2010 ) has been successfully employed before, yet in this study we targeted an intracellular protein. These observations led us to conclude that RTN1A is promoting elongation of dendrites in rLCs.…”

Section: Discussionmentioning

confidence: 99%

Interoperability of RTN1A in dendrite dynamics and immune functions in human Langerhans cells

Cichoń

Pfisterer

Leitner

et al. 2022

eLife

View full text Add to dashboard Cite

Skin is an active immune organ where professional antigen-presenting cells such as epidermal Langerhans cells (LCs) link innate and adaptive immune responses. While Reticulon 1A (RTN1A) was recently identified in LCs and dendritic cells in cutaneous and lymphoid tissues of humans and mice, its function is still unclear. Here, we studied the involvement of this protein in cytoskeletal remodeling and immune responses toward pathogens by stimulation of Toll-like receptors (TLRs) in resident LCs (rLCs) and emigrated LCs (eLCs) in human epidermis ex vivo and in a transgenic THP-1 RTN1A+ cell line. Hampering RTN1A functionality through an inhibitory antibody induced significant dendrite retraction of rLCs and inhibited their emigration. Similarly, expression of RTN1A in THP-1 cells significantly altered their morphology, enhanced aggregation potential, and inhibited the Ca2+ flux. Differentiated THP-1 RTN1A+ macrophages exhibited long cell protrusions and a larger cell body size in comparison to wild-type cells. Further, stimulation of epidermal sheets with bacterial lipoproteins (TLR1/2 and TLR2 agonists) and single-stranded RNA (TLR7 agonist) resulted in the formation of substantial clusters of rLCs and a significant decrease of RTN1A expression in eLCs. Together, our data indicate involvement of RTN1A in dendrite dynamics and structural plasticity of primary LCs. Moreover, we discovered a relation between activation of TLRs, clustering of LCs, and downregulation of RTN1A within the epidermis, thus indicating an important role of RTN1A in LC residency and maintaining tissue homeostasis.

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Laser‐assisted epicutaneous immunization to target human skin dendritic cells

Cited by 7 publications

References 57 publications

Targeted delivery of a vaccine protein to Langerhans cells in the human skin via the C‐type lectin receptor Langerin

Targeted delivery of a vaccine protein to Langerhans cells in the human skin via the C‐type lectin receptor Langerin

Interoperability of RTN1A in dendrite dynamics and immune functions in human Langerhans cells

Interoperability of RTN1A in dendrite dynamics and immune functions in human Langerhans cells

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