Meeting Report of the 16th International Langerhans Cell Workshop: Recent Developments in Langerhans Cell and Skin Dendritic Cell Biology and ...
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MEETING REPORT
Meeting Report of the 16th International Langerhans
Cell Workshop: Recent Developments in
Langerhans Cell and Skin Dendritic Cell Biology and
their Therapeutic Application
Björn E. Clausen1, Nikolaus Romani2 and Patrizia Stoitzner2
Journal of Investigative Dermatology (2020) 140, 1315e1319; doi:10.1016/j.jid.2020.02.022
Introduction the fetal tissue, at a time when innate persist in the epidermis, indicating that
The 16th International Workshop on immunity dominates over adaptive im- lack of E-cadherin alone does not
Langerhans Cells (LCs) was organized munity (Popescu et al., 2019). Florent trigger LC emigration (Brand et al.,
by Björn E. Clausen with the help of Ginhoux (Singapore Immunology 2020). Using a mouse model, in
Patrizia Stoitzner and Nikolaus Romani Network, Singapore) gave an overview which neoantigen ovalbumin is
in Budenheim near Mainz, Germany. on his recent work on tissue niche- expressed exclusively in LCs (Strandt
From 3rd through 6th October 2019, specific subsets of macrophages, et al., 2017), Helen Strandt (University
more than 100 scientists from all over exemplary in the lung (Chakarov et al., of Salzburg, Austria) proved that LCs in
the world presented their cutting-edge 2019). He put forward the notion that steady state induce tolerance that is
work and technological advances in the main function of macrophages may able to suppress allergic airway re-
the field of skin immunity with a special be maintenance of tissue homeostasis sponses. Dan Kaplan (University of
focus on LCs and dermal dendritic cells rather than phagocytosis of bacteria. Pittsburgh, PA) presented a possible
(DCs). Novel insights into the develop- Moreover, he extended our perception explanation for the longstanding, unre-
ment and homeostasis of LCs and of cDC1s in skin bacterial infection solved discrepancy in the intensity of
dermal DCs and their respective func- beyond antigen presentation to the contact hypersensitivity (CHS) re-
tional roles in health and disease were regulation of neutrophil recruitment sponses between the various LC-
discussed. Regarding translation into (Janela et al., 2019) and presented a depletion mouse models available
the clinic, several therapeutic in- novel monocyte fate mapping mouse (Clausen and Stoitzner, 2015). Specif-
terventions using DC for the treatment model on the basis of Ms4a3 expression ically, long-term depletion of LC by
of skin diseases and cancer were pre- (Liu et al., 2019). Kristin Seré (RWTH repeated diphtheria toxin injections in
sented. The workshop gave particularly Aachen University, Germany) empha- Langerin-DTR or constitutively, in
young researchers a great opportunity sized that LCs undergo mesenchymal- Langerin-DTA mice (Kaplan, 2017)
to meet and interact with leading ex- epithelial transition for long-term resi- leads to a loss of epidermal sensory
perts in the field of myeloid cell biology dency in the epidermis (Hieronymus afferent nerves. The absence of these
and skin immunology. et al., 2015). Id2 is required for nerves results in hyperactive mast cell
mesenchymal-epithelial transition in function. As a consequence, mice with
LC ontogeny or development, skin DC LCs, and consequently, lack of Id2 long-term ablation of LCs or mice spe-
network, and skin homeostasis mediates LC emigration from the skin. cifically lacking just these neurons
Muzlifah Haniffa (Newcastle Univer- Further novel insights on LC homeo- develop exaggerated irritant dermatitis,
sity, Newcastle-upon-Tyne, United stasis came from Vincent Flacher (Uni- CHS, and host defense against Staphy-
Kingdom), a member of the Human versity of Strasbourg, France), who lococcus aureus. These observations
Cell Atlas consortium (Regev et al., demonstrated that LCs require auto- support Florent Ginhoux’s notion that
2017), reported on the perspectives phagy for their maintenance in the skin LCs, which have a common embryonic
and possibilities of mapping human and unperturbed lipid metabolism. origin with macrophages, contribute to
development at single-cell resolution Anna Brand (University of Mainz, Ger- maintain skin homeostasis (see above),
(Behjati et al., 2018). She presented many) discovered that E-cadherin‒ in addition to their well-known anti-
single-cell RNA-sequencing data of deficient LCs display a dramatically gen-presenting DC function. Moreover,
fetal and adult skin and demonstrated altered morphology with more rounded the novel data put forward by the
how the tissue influences marker cell bodies as well as less and shorter Kaplan laboratory extend initial reports
expression on immune cells already in dendrites. Unexpectedly, these LCs that long-term absence of LCs impairs
1
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; and 2Department of
Dermatology, Venereology & Allergology, Medical University of Innsbruck, Innsbruck, Austria
Correspondence: Björn E. Clausen, Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz,
Langenbeckstrasse 1, D-55131 Mainz, Germany. E-mail: bclausen@uni-mainz.de
Accepted manuscript published online 19 March 2020; corrected proof published online 10 May 2020
ª 2020 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. www.jidonline.org 1315BE Clausen et al.
LC2019 Meeting Report
epidermal barrier function (Lee et al., including innate lymphoid cells (ILCs), common cutaneous pathogen that binds
2019) and alters the gene expression as emphasized by Tetsuro Kobayashi to — interestingly only human — lan-
profile of keratinocytes and dendritic (RIKEN, Center for Integrative Medical gerin, leading to activation of LCs as
epidermal T cells (Su et al., 2020). On Sciences, Yokohama, Japan). Investi- recently published by Nina van Sorge
the other hand, why acute depletion of gating the various ILC subtypes in the (Utrecht University, The Netherlands)
LCs in essentially the same mice also skin, he observed a preferred localiza- (van Dalen et al., 2019). Moreover, skin
leads to enhanced CHS responses (Bobr tion of ILC3s in the epidermis and ILC2s LCs are activated by Pam3Cys from
et al., 2010), in contrast to other in the dermis. ILC3s are recruited to the S. aureus, promoting a T helper 2 (Th2)
inducible LC-depletion models epidermis through hair follicles and response as reported by Yi Pan (Univer-
(Clausen and Stoitzner, 2015), remains regulate sebaceous glands and as a sity of Bonn, Germany). The application
elusive. Not only is the LC network consequence, the composition of the route for S. aureus determines the sub-
important in homeostasis; the T cells microbiota (Kobayashi et al., 2019). LCs sequent immune response as illustrated
present in the skin are too. Iris Gratz are also present in the oral mucosa by Sandrine Henri (Aix Marseille Uni-
(University of Salzburg, Austria) where they are even more exposed to versity, France). While topical applica-
analyzed the life cycle of tissue-resident commensals and pathogens. Interest- tion leads to mild inflammation and
memory T cells. Using a skin xenograft ingly, in the tongue, LCs accumulate in mixed Th1 and/or Th17 responses, in-
model, she reported that human tissue- germ-free mice, indicating that they tradermal injection triggers a Th1
resident memory T cells can leave skin might leave the epithelium owing to response after translocation of bacteria to
grafts, recirculate in mouse blood, and contact with commensals as shown by lymph nodes. Both LCs and cDC1s are
home to another human skin transplant Yael Horev (Hebrew University, Jeru- dispensable for the T-cell response
(Klicznik et al., 2019). Moreover, tissue- salem, Israel). Moreover, they are lost against S. aureus, whereas cDC2s induce
resident memory T cells are Candida- during aging due to upregulation of the Th17 response. A novel Malassezia
specific, and they proliferate locally in inflammatory cytokines and chemo- infection mouse model to investigate the
response to immunization with kines, although the epithelium can be rapid Th17 response mediated by ab and
Candida-loaded DCs. Sangbum Park repopulated by monocytic precursors. gd T cells as well as ILCs was presented
(Yale University, New Haven, CT) LCs are exposed to multiple patho- by Florian Sparber (University of Zürich,
investigated the conspicuous spatial gens, such as viruses, fungi, and bacteria. Switzerland) (Sparber et al., 2019).
organization and homeostasis of im- As outlined by Teunis Geijtenbeek (Uni- Nevertheless, the main DC subset
mune cells in the skin, specifically LCs versity of Amsterdam, The Netherlands), inducing these Th17 responses has not
in the epidermis. By cutting-edge two- LCs have developed smart ways to elim- been elucidated yet. Many workshop
photon live imaging techniques com- inate viruses. The restriction factor presentations emphasized the need for
bined with cell ablation models, he TRIM5a prevents HIV replication only in novel infection models, not least for the
revealed and strikingly visualized a LCs but not in other DC subtypes as it is purpose of a desirable reduction in ani-
mutually repulsive behavior of LCs that located in the Birbeck granules. This mal experimentation. Indeed, such a
ensured their typical network pattern. elimination process is insufficient for prototypic model has been established
The molecular mechanism for this many of the so-called transmitted by Doris Wilflingseder (Medical Univer-
behavior remains to be determined. founder viruses, that is, those HIV strains sity of Innsbruck, Austria). It is a human
Another novel aspect of skin homeo- that, among a variety of other strains, three-dimensional lung epithelial cell
stasis was presented by Shruti Naik finally enter the patients (Hertoghs et al., culture model that can be seeded with
(New York University, NY), who re- 2019). This underscores the dual function immune cells to investigate DC- and/or
ported that inflammation-linked cuta- of LCs in HIV infection: virus elimination macrophage-pathogen interactions
neous insults instruct tissue cells, such and virus transmission to CD4 T cells. ex vivo (Chandorkar et al., 2017).
as keratinocytes, to retain open chro- Interestingly, during experimental coin- Regarding HIV treatment, Sylvain
matin areas where genes for tissue fection with the bacterium Prevotella, Cardinaud (Vaccine Research Insti-
regeneration, cancer, and apoptosis are occurring in the vaginal microbiota dur- tute, Créteil, France) has developed an
located (Naik et al., 2017). Thus, this ing bacterial vaginosis, LCs take up HIV LC-based immunotherapy with anti-
“inflammatory memory” can be bene- but do not eliminate but rather store it langerin antibody conjugated to HIV
ficial because tissue regeneration and intracellularly for subsequent trans- envelope antigen that was tested in
healing occur faster, but it can also mission to other immune cells. Leanne human Langerin-DTR mice and non-
harm the skin because after resolution Helgers from the same working group human primates (macaques). Without
of inflammation, subsequent chemical reported that Dengue virus infects LCs addition of adjuvant, a strong activa-
carcinogenesis is accelerated. and can be transmitted to other DCs, tion of T follicular helper cells and
partly mediated by langerin. Yonatan antibodies specific for HIV-1 could be
Microbiota and pathogen interactions Ganor (Cochin Institute, Centre National detected. In contrast, no cytotoxic T-
with skin and mucosal DCs De La Recherche Scientifique, Paris, cell response could be measured. This
LCs are located in the outmost layer of France) unraveled a role for capsaicin, sheds new light on a possible role of
the skin and thus have access to mi- the spicy ingredient in chili peppers that LCs in the humoral response (Bouteau
croorganisms on the skin surface or stimulates cutaneous nociceptors to et al., 2019).
during infection. Several other immune secrete CGRP, which in turn inhibits In summary, workshop contributions
cell types are also present in the skin, infection of LCs by HIV-1. S. aureus is a emphasized that the understanding of
1316 Journal of Investigative Dermatology (2020), Volume 140BE Clausen et al.
LC2019 Meeting Report
commensal and/or pathogen in- reported that tertiary lymphoid struc- myeloid precursors recapitulates an LC
teractions with LCs and other skin DCs tures, originally detected in inflamma- histiocytosis-like phenotype in mice,
is crucial to develop future strategies for tory experimental settings (“iSALT”) and MAPK inhibitors are now clinically
immunization and therapy. LCs interact (Natsuaki and Kabashima, 2016), also used for treatment (reviewed in Allen
with multiple pathogens with very develop in the upper dermis of human et al., 2018). Cells in LC histiocytosis
diverse, context-dependent immuno- atopic dermatitis and psoriatic skin. The lesions express langerin and CD1a and
logic outcomes; however, Th17 re- high endothelial venules in these develop from different cell types, pri-
sponses seem to be crucial for clearing structures are surrounded by DCs and marily CD1cþ myeloid DCs, but
bacterial and fungal infections. Novel recruit memory T cells. In systemic possibly also from CD14þ cells (Lim
three-dimensional epithelium models lupus erythematosus-affected skin, et al., 2020). The functional role of
will help to further elucidate the close Theresa Lu (Hospital for Special Sur- skin DC in tumor immunity was dis-
interactions between (human) immune gery, New York, NY) investigated the cussed by Tanja de Gruijl (University
cells and pathogens in the tissue. reasons for the higher photosensitivity. Medical Center Amsterdam, The
LCs protect UVR-damaged keratino- Netherlands). Owing to the recruitment
LCs and/or DCs in the pathogenesis cytes from apoptosis by providing EGFR of suppressive CD14þ macrophage-like
and regulation of inflammatory skin ligands and in systemic lupus erythe- cells, melanoma tumors exert an early
diseases matosus this function is impaired negative effect on anti-tumor immunity
LCs and dermal DCs also play crucial causing photosensitivity (Shipman in the sentinel lymph nodes that can be
roles in various inflammatory skin dis- et al., 2018). Further dissecting the overcome by intratumoral injection of
eases, such as CHS, psoriasis, and sys- mechanisms of LC-induced immuno- the TLR9 ligand CpG, leading to pro-
temic lupus erythematosus. Michel suppression, Karin Loser (University of longed recurrence-free survival (van
Gilliet (University Hospital, Lausanne, Münster, Germany) observed that in a den Hout et al., 2017; Koster et al.,
Switzerland) highlighted the impor- murine UV-irradiation model, LCs 2017). Thus, TLR ligation could be an
tance of plasmacytoid DCs, which are upregulate PD-L1, and aryl- alternative approach to checkpoint
recruited to inflamed skin through the hydrocarbon receptor leading to their blockade therapy in an early adjuvant
neutrophil-produced chemokine migration to lymph nodes where they setting. Avi-Hai Hovav (Hebrew Uni-
CXCL10 (IP-10) during psoriasis induce Tregs. Sayuri Yamazaki (Nagoya versity, Jerusalem, Israel) described LCs
(Conrad and Gilliet, 2018). He pre- City University, Nagoya, Japan) re- in the tongue epithelium (Hovav, 2018)
sented a novel feature of this chemo- ported that Tregs are expanded in UV- and reported that they play an essential
kine as it binds directly to DNA, thus exposed skin by langerine CD11bþ role in inhibiting oral squamous cell
forming CXCL10-DNA complexes that dermal DC subsets (Yamazaki et al., carcinoma in a chemical carcinogen-
trigger the pathogenic type-1 IFN 2018) and that the UV-expanded Tregs esis model as has been reported before
response. I-hsin Su (Nanyang Techno- play a key role in skin homeostasis. The in the skin (Ortner et al., 2017). A
logical University, Singapore) reported expression of CD5 in subsets of human continuous decline of LCs in the tongue
that the essential integrin adaptor talin1 DCs and/or LCs indicates that these of aged mice could be a reason for the
was required for the formation of novel cells are superior in CTL, Th1, and Th22 higher susceptibility to carcinogenesis
preassembled TLR complexes in DC at induction and higher numbers of CD5þ in elderly individuals.
steady state through direct interaction LCs and dermal DCs are present in With regard to DC-based therapeutic
with MyD88 and PIP5K, which were psoriatic lesions as shown by Eynav strategies, James Young (Memorial
required for the MyD88-dependent toll- Klechevsky (Washington University Sloan Kettering Cancer Center, New
like receptor signalosome assembly School of Medicine, St. Louis, MO) York, NY) reported that most patients in
during DC activation in CHS and anti- (Korenfeld et al., 2017). BMP7, a new a previously published clinical study
bacterial responses (Lim et al., 2020). player in psoriasis, was reported by using human CD34þ-derived LCs
Karsten Mahnke (University of Heidel- Tommaso Sconocchia (Medical Uni- transfected with mRNA encoding mu-
berg, Germany) stressed the decisive versity of Graz, Austria) to be expressed rine TRP2, many of whom had received
role of adenosine, produced by DCs by keratinocytes. Known to be a growth additional interventions like checkpoint
and/or LCs through surface CD73, for factor that is important for human LC inhibitors, were still alive and
the generation of hyporeactive differentiation (Borek et al., 2020), exceeding expected outcomes with
(tolerant) T cells during CHS (Silva- BMP7 may thus contribute to psoriatic either modality alone. This highlights
Vilches et al., 2019). Kenji Kabashima inflammation. the continued relevance of LCs as im-
(Kyoto University, Kyoto, Japan) char- munogens for cancer immunotherapy
acterized the skin T-cell pool in more Skin DCs in cancer and DCs-based (Chung et al., 2017). Similarly, prom-
detail and revealed that, intriguingly, it therapeutic strategies ising results are being observed in an
contains up to 30% regulatory T cells Carl Allen (Texas Children’s Cancer ongoing study of patients with myeloma
(Tregs), which can recirculate through Center, Houston, TX) reported on the treated with LC electroporated with
the lymph nodes and suppress CHS. latest developments in understanding mRNAs encoding three myeloma anti-
These Tregs produce IL-10 that blocks the pathogenesis of LC histiocytosis. gens. Still, in vitro generated LCs or
DC migration, and their depletion from BRAFV600E or other activating somatic dermal DCs are not entirely over-
the skin improves CD8þ T-cell and hu- MAPK mutations are detected in almost lapping with their counterparts in situ,
moral responses. Furthermore, he all cases. MAPK hyperactivation in as determined by CyTOF and single-
www.jidonline.org 1317BE Clausen et al.
LC2019 Meeting Report
cell RNA-sequencing. Anastasia Pro- immunotherapy at a large scale. With Borek I, Köffel R, Feichtinger J, Spies M, Glitzner-
Zeis E, Hochgerner M, et al. BMP7 aberrantly
kopi (Medical University of Innsbruck, new mouse models, new sorting stra-
induced in the psoriatic epidermis instructs
Austria) discussed a spontaneous mel- tegies for the various skin DC subsets, inflammation-associated Langerhans cells.
anoma mouse model with a specific new analytic tools for the analysis of J Allergy Clin Immunol 2020;145:1194e1207.
loss of skin cDC2s in tumors that could minute-cell populations and even sin- e11.
be overcome by treatment with Flt3L gle cells, and most importantly, with Bouteau A, Kervevan J, Su Q, Zurawski SM,
Contreras V, Dereuddre-Bosquet N, et al. DC
and a DC-activating adjuvant. In com- more studies on human cells and with subsets regulate humoral immune responses by
bination with checkpoint blockade an- human diseases and patients, we will supporting the differentiation of distinct Tfh
tibodies, T-cell function in tumors and be able to illuminate these remaining cells. Front Immunol 2019;10:1134.
draining lymph nodes could be boos- mysteries in the future. Ultimately, this Brand A, Diener N, Zahner SP, Tripp C,
Backer RA, Karram K, et al. E-cadherin is
ted. An alternative approach developed will benefit medicine and thus industry dispensable to maintain Langerhans cells in the
by Christoph Rademacher’s laboratory as well as society. epidermis. J Invest Dermatol 2020;140:
(Max Planck Institute of Colloids and The 17th International Workshop on 132e42.e3.
Interfaces, Potsdam, Germany) uses a Langerhans Cells, organized by Avi-Hai Chakarov S, Lim HY, Tan L, Lim SY, See P, Lum J,
glycomimetic langerin ligand conju- Hovav (Jerusalem) and Eynav Klechev- et al. Two distinct interstitial macrophage
populations coexist across tissues in specific
gated to liposomes that can carry any sky (St. Louis) with the help of Yonatan
subtissular niches. Science 2019;363:
drug or antigen (Wamhoff et al., 2019). Ganor (Paris), will take place in the fall eaau0964.
These langerin-liposomes are specif- of 2021 in Jerusalem, Israel. (www.lc2 Chandorkar P, Posch W, Zaderer V, Blatzer M,
ically incorporated into LCs and repre- 021.org) Steger M, Ammann CG, et al. Fast-track devel-
sent a promising novel approach for opment of an in vitro 3D lung/immune cell
ORCIDs model to study Aspergillus infections. Sci Rep
LC-based immunotherapy of skin dis- 2017;7:11644.
eases or cancer. Besides this, exploiting Björn E. Clausen: http://orcid.org/0000-
0002-2484-7842 Chung DJ, Carvajal RD, Postow MA, Sharma S,
these liposomes, cytostatic drugs could Pronschinske KB, Shyer JA, et al. Langerhans-
Nikolaus Romani: http://orcid.org/0000-
be specifically delivered to LC histio- 0003-1614-9128 type dendritic cells electroporated with TRP-2
cytosis lesions to destroy proliferating Patrizia Stoitzner: http://orcid.org/0000- mRNA stimulate cellular immunity against
0002-8488-6704 melanoma: results of a phase I vaccine trial.
tumor cells. The question about the best Oncoimmunology 2017;7:e1372081.
means of delivering DC-adjuvant was Clausen BE, Stoitzner P. Functional specialization
Conflict of Interest
addressed by Juliana Idoyaga (Stanford The authors state no conflict of interest. of skin dendritic cell subsets in regulating T cell
University School of Medicine, Stan- responses. Front Immunol 2015;6:534.
ford, CA). As a rational basis, she pre- ACKNOWLEDGMENTS Conrad C, Gilliet M. Psoriasis: from pathogenesis
The authors apologize to all colleagues whose to targeted therapies. Clin Rev Allergy Immunol
sented a detailed CyTOF analysis of
valuable contributions have not been mentioned 2018;54:102e13.
DCs and defined a subset of transitional owing to space constraints. The authors would like Hertoghs N, Nijmeijer BM, van Teijlingen NH,
DCs (Axlþ DCs) in humans and mice to emphasize that all presentations were of great Fenton-May AE, Kaptein TM, van Hamme JL,
(Leylek et al., 2019). As a novel twist of interest and high quality and therefore signifi- et al. Sexually transmitted founder HIV-1 vi-
cantly contributed to the success of the workshop. ruses are relatively resistant to Langerhans cell-
targeting strategies, not only antigens The authors are grateful for the generous support mediated restriction. PLoS One 2019;14:
but also adjuvants are being coupled to from the German Science Foundation (Deutsche e0226651.
DC-specific antibodies (e.g., DEC205). Forschungsgemeinschaft, CL 419/6-1), without
which LC2019 would not have been possible, as Hieronymus T, Zenke M, Baek JH, Seré K. The
Indeed, double-stranded DNA linked to clash of Langerhans cell homeostasis in skin:
well as the European Federation of Immunological
anti-DEC205 boosted tumor immunity Societies (EFIS) and European Journal of Immu- should I stay or should I go? Semin Cell Dev
in a mouse model. nology (EJI), which was essential to enable, in Biol 2015;41:30e8.
particular, young scientists to attend. The authors Hovav AH. Mucosal and skin Langerhans cells -
also thank all partners from industry who finan- nurture calls. Trends Immunol 2018;39:
Conclusion
cially supported the workshop and presented their 788e800.
The presence of more than 100 scien- latest products and state-of-the-art equipment. Janela B, Patel AA, Lau MC, Goh CC, Msallam R,
tists from all over the world working on They thereby helped substantially to make atten- Kong WT, et al. A subset of type I conventional
various aspects of LC and DC biology dance affordable for many students and residents. dendritic cells controls cutaneous bacterial in-
For the full list of sponsors please see www.lc201 fections through VEGFa-mediated recruitment of
made LC2019 a very exciting meeting. 9.de. neutrophils. Immunity 2019;50:1069e83.e8.
The functions of LCs in the skin im-
Kaplan DH. Ontogeny and function of murine
mune system in vivo seem to be mani- Author Contributions epidermal Langerhans cells. Nat Immunol
fold. Clearly, they are involved in All authors equally contributed to the conceptu- 2017;18:1068e75.
alization and writing of this Meeting Report.
immune responses against pathogens Klicznik MM, Morawski PA, Höllbacher B,
and skin tumors, but also perform a Varkhande SR, Motley SJ, Kuri-Cervantes L,
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