Bedoui S, Whitney PG, Waithman J et al.Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat Immunol 10:488-495

The Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia.
Nature Immunology (Impact Factor: 24.97). 05/2009; 10(5):488-95. DOI: 10.1038/ni.1724
Source: PubMed

ABSTRACT Skin-derived dendritic cells (DCs) include Langerhans cells, classical dermal DCs and a langerin-positive CD103(+) dermal subset. We examined their involvement in the presentation of skin-associated viral and self antigens. Only the CD103(+) subset efficiently presented antigens of herpes simplex virus type 1 to naive CD8(+) T cells, although all subsets presented these antigens to CD4(+) T cells. This showed that CD103(+) DCs were the migratory subset most efficient at processing viral antigens into the major histocompatibility complex class I pathway, potentially through cross-presentation. This was supported by data showing only CD103(+) DCs efficiently cross-presented skin-derived self antigens. This indicates CD103(+) DCs are the main migratory subtype able to cross-present viral and self antigens, which identifies another level of specialization for skin DCs.

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Available from: Liv Eidsmo, Aug 28, 2015
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    • "The death of antigen-carrying skin-derived DCs would also be expected to accelerate antigen transfer to LN-resident DCs. The priming capability of CD103−DDCs in relation to CD4+ T cells is higher than for CD8+ T cells44, while CD8α+ LN-resident DCs are known to be effective antigen-presenting cells for CD8+ T cells34445, with high phagocytic activity46. Thus, it is possible that the influx of a large number of apoptotic antigen-carrying CD103−DDCs triggers accelerated phagocytosis and cross priming by CD8α+ LN-resident DCs. "
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    ABSTRACT: Skin-derived dendritic cells (DCs) play a crucial role in the maintenance of immune homeostasis due to their role in antigen trafficking from the skin to the draining lymph nodes (dLNs). To quantify the spatiotemporal regulation of skin-derived DCs in vivo, we generated knock-in mice expressing the photoconvertible fluorescent protein KikGR. By exposing the skin or dLN of these mice to violet light, we were able to label and track the migration and turnover of endogenous skin-derived DCs. Langerhans cells and CD103(+)DCs, including Langerin(+)CD103(+)dermal DCs (DDCs), remained in the dLN for 4-4.5 days after migration from the skin, while CD103(-)DDCs persisted for only two days. Application of a skin irritant (chemical stress) induced a transient >10-fold increase in CD103(-)DDC migration from the skin to the dLN. Tape stripping (mechanical injury) induced a long-lasting four-fold increase in CD103(-)DDC migration to the dLN and accelerated the trafficking of exogenous protein antigens by these cells. Both stresses increased the turnover of CD103(-)DDCs within the dLN, causing these cells to die within one day of arrival. Therefore, CD103(-)DDCs act as sentinels against skin invasion that respond with increased cellular migration and antigen trafficking from the skin to the dLNs.
    Scientific Reports 08/2014; 4:6030. DOI:10.1038/srep06030 · 5.58 Impact Factor
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    • "In the epidermis, Langerhans cells (LC) form a dense network of DC capable of capturing antigen and migrating to the LN after traversing the basement membrane into the dermis. In mice, LC appear to be particularly efficient at tolerance induction and the formation of regulatory T cells (Tregs) (6, 7), whereas they are dispensable for induction of CD8 T cell responses to infections (8–10). Skin macrophages also populate the dermis and include perivascular macrophages that are distributed along post-capillary venules and can assist with the recruitment of neutrophils from the blood (11). "
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    ABSTRACT: The skin is a large and complex organ that acts as a critical barrier protecting the body from pathogens in the environment. Numerous heterogeneous populations of immune cells are found within skin, including some that remain resident and others that can enter and exit the skin as part of their migration program. Pathogen-specific CD8(+) T cells that persist in the epidermis following infection are a unique population of memory cells with important roles in immune surveillance and protective responses to reinfection. How these tissue-resident memory T cells form in the skin, the signals controlling their persistence and behavior, and the mechanisms by which they mediate local recall responses are just beginning to be elucidated. Here, we discuss recent progress in understanding the roles of these skin-resident T cells and also highlight some of the key unanswered questions that need addressing.
    Frontiers in Immunology 07/2014; 5:332. DOI:10.3389/fimmu.2014.00332
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    • "Here we report that BCL6 protein levels are high in steady-state migratory cDCs, but low in CD11cint I-Ahi cDCs after exposure to LPS or adjuvants, suggesting that the transcriptional repressor BCL6 might play a role in the induction of immune tolerance of self-antigens in the steady state. In line with this idea, the most intense BCL6 expression is observed in the steady-state splenic CD8α+ and LN CD103+ cDC subpopulations (data not shown), subsets reported to cross-present self-antigens from dead cells to induce self-tolerance [35], [36]. "
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    ABSTRACT: The transcriptional repressor BCL6 plays an essential role in the development of germinal center B cells and follicular helper T cells. However, much less is known about the expression and function of BCL6 in other cell types. Here we report that during murine dendritic cell (DC) ontogeny in vivo, BCL6 is not expressed in bone marrow hematopoietic stem cells, common DC precursors and committed precursors of conventional DCs (pre-cDCs), but is elevated in peripheral pre-cDCs. BCL6 protein levels rise as pre-cDCs differentiate into cDCs in secondary lymphoid organs. Elevated protein levels of Bcl6 are observed in all cDC subsets, with CD8α+ cDCs displaying the greatest levels. Co-staining of Ki-67 revealed BCL6hi cDCs to be more proliferative than BCL6lo cDCs. After adjuvant inoculation, BCL6 levels are significantly reduced in the CD11cint MHC class IIhi CD86hi cDCs. Activation-induced BCL6 reduction correlated with reduced proliferation. A LPS injection study further confirmed that, in response to microbial stimuli, BCL6 levels are dynamically regulated during the maturation of CD11cint MHC class IIhi splenic cDCs. This reduction of BCL6 levels in cDCs does not occur after LPS injection in MyD88-/- TRIF-/- mice. Thus, regulation of Bcl6 protein levels is dynamic in murine cDCs during development, maturation and activation in vivo.
    PLoS ONE 06/2014; 9(6):e101208. DOI:10.1371/journal.pone.0101208 · 3.23 Impact Factor
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