A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury
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Abstract
Abstract Embryo-derived Langerhans cells (eLC) are maintained within the sealed epidermis without contribution from circulating cells. When the network is perturbed by transient exposure to ultra-violet light, short-term LC are temporarily reconstituted from an initial wave of monocytes, but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this mechanism is relevant to immune-pathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where allo-reactive T cells directly target eLC, we have asked if and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of the long-term LC in this context. Destruction of eLC leads to recruitment of a single wave of monocytes which engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM + precursors. Monocyte-derived LC acquire the capacity of self-renewal, and turn-over in the epidermis was remarkably similar to that of steady state eLC. However, we have identified a bottleneck in the differentiation and survival of epidermal monocytes, which together with the slow turn-over of mature LC limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin. Highlights Immune injury leads to recruitment of a single wave of monocytes to replace resident Langerhans cells (LC). DC lineage cells cannot become long-term replacement LC. The size of the re-emerging network is controlled by density-dependent division of mature LC. Immune injury and inefficient repopulation by monocyte-derived cells lead to a permanently altered LC niche.
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Murine studies show that monocytes can temporarily replace embryonic macrophages when inflammation causes a cell deficit, allowing macrophage populations to proliferate.
“To add further complications to the field of macrophage ontogeny, murine studies have shown that there are situations where monocytes can temporarily replace embryonically derived macrophages when there is a deficit in the cell number due to an inflammatory event, to allow time for the macrophage populations to proliferate (55).”
From The impact of ageing on monocytes and macrophages (2021) · cites this paper as [55]
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- [47]Burnham KPaA DR Model Selection and Inference: A Practical Information-Theoretical Approach. 2nd ed. New YOrk: Springer-Verlag; 2002.
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The CD14++CD16+ monocyte subset is expanded and controls Th1 cell development in Graves' disease
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Tissue-resident, extravascular Ly6c− monocytes are critical for inflammation in the synovium
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Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling
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Niche rather than origin dysregulates mucosal Langerhans cells development in aged mice
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Monocytes give rise to Langerhans cells that preferentially migrate to lymph nodes at steady state
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Tissue‐specific antigen‐presenting cells contribute to distinct phenotypes of allergy
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Friend or foe? — Janus Langerhans cells in skin immunity and promising clinical application
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Pacifico, P., George, D., Jayaraj, N. D., Ren, D., Coy-Dibley, J. S., Belmadani, A. A., Veronesi, S., Anđelić, M., Cartelli, D., Devigili, G., et al. (2026) · Journal of Clinical Investigation · doi:10.1172/jci192328 · Cited by 4 · see citing works
Olexen, C. M., Risnik, D., Lava, M. C., Vecchia, G. L. D., Rosso, D. A., Errasti, A. E., & Silva, E. A. C. (2024) · Clinical Immunology · doi:10.1016/j.clim.2024.110203 · Cited by 4 · see citing works
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TNF-α and IL-1β Do Not Induce Langerhans Cell Migration by Inhibiting TGFβ Activation
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Niche-specific macrophage loss promotes skin capillary agingPreprint
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- Authors
- Ferrer, I. R., West, H. C., Henderson, S., Ushakov, D. S., Santos e Sousa, P., Strid, J., Chakraverty, R., Yates, A. J., & Bennett, C. L.
- Affiliations
- University College London (GB)
- King's College London (GB)
- Institute for Immunity and Transplantation, Division of Infection and Immunity, University College London, London NW3 2PF, UK and Cancer Institute Department of Haematology, Division of Cancer Studies, University College London, London WC1E 6DD, UK.
- Imperial College London (GB)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Bennett, Clare L.
- ORCID
- Venue
- Science Immunology
- Published
- 2019-08-02
- Volume
- 4
- Issue
- 38
- ISSN
- 2470-9468 (ISSN-L)
- PMC
- PMC6894529
- OpenAlex
- W2969818451
- Cited by
- 61
- References
- 77
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 9 · 2023: 9 · 2022: 5 · 2021: 14 · 2020: 12 · 2019: 2
- FWCI
- 3.30
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Science Immunology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- National Institutes of Health (R01 AI093870)
- Wellcome (100156)
- Medical Research Council (1450227)
- Biotechnology and Biological Sciences Research Council (BB/L001608/1)
- Bloodwise (17007)
- Royal Free Charity (174418)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- Langerhans cells, monocytes, epidermis, immune injury, tissue repair, Langerhans cell differentiation, skin immune homeostasis, tissue-resident macrophages
- MeSH terms
- Animals, Cells, Cultured, Humans, Langerhans Cells, Male, Mice, Inbred C57BL, Mice, Transgenic, Monocytes, Mice, Knockout, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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