Murine epidermal Langerhans cells and langerin-expressing dermal dendritic cells are unrelated and exhibit distinct functions

Abstract

A new langerin ؉ DC subset has recently been identified in murine dermis (langerin ؉ dDC), but the lineage and functional relationships between these cells and langerin ؉ epidermal Langerhans cells (LC) are incompletely characterized. Selective expression of the cell adhesion molecule EpCAM by LC allowed viable LC to be easily distinguished from langerin ؉ dDC in skin and lymphoid tissue and ex vivo as well. Differential expression of EpCAM and langerin revealed the presence of at least 3 distinct skin DC subsets. We determined that LC and langerin ؉ dDC exhibit different migratory capabilities in vitro and repopulate distinct anatomic compartments in skin at different rates after conditional depletion in vivo. Langerin ؉ dDC, in contrast to LC, did not require TGF␤1 for development. Carefully timed gene gun immunization studies designed to take advantage of the distinct repopulation kinetics of langerin ؉ dDC and LC revealed that langerin ؉ dDC were required for optimal production of ␤-galactosidase-specific IgG2a/c and IgG2b in the acute phase. In contrast, immunization via LC-deficient skin resulted in persistent and strikingly reduced IgG1 and enhanced IgG2a Ab production. Our data support the concepts that LC and langerin ؉ dDC represent distinct DC subsets that have specialized functions and that LC are important immunoregulatory cells. The presence of at least 3 functionally distinct skin DC subsets may have particular relevance for vaccines that are administered epicutaneously.EpCAM ͉ gene gun ͉ langerin ͉ TGF-beta T he remarkable phenotypic heterogeneity of DC, both between and within certain tissues, has been long recognized. To date, however, it has been possible to clearly relate DC phenotype to DC function in only a few instances, even in mice. For example, plasmacytoid DC are recognized as the primary source of virus-induced type I IFN (1), CD8␣ ϩ lymph node DC are largely responsible for cross-presentation of cell-associated antigen to CD8 T cells (2-4), and 33D1-reactive (DCIR2 ϩ ) splenic DC (as compared with CD205 ϩ DC) preferentially stimulate CD4 T cells (5). Epidermal Langerhans cells (LC) represent perhaps the most striking example of an extensively studied tissue DC subpopulation whose function is incompletely understood.LC have long been thought to play pivotal roles in initiating immunity by acquiring antigens that are encountered in skin, migrating to draining LN after activation, and stimulating antigen-specific T cells (6). However, recent studies suggested that LC do not function as essential antigen-presenting cells for anti-viral immune responses (2, 7) or for contact hypersensitivity reactions (8-12) in established murine models. Studies of LC have been challenging, in part, because readily detectable cell surface proteins that are constitutively expressed by epidermal LC and LC that have emigrated from epidermis have not been well recognized. The C-type lectin langerin has been regarded as a pathognomonic LC marker, but recent studies suggest that this protein is present in at le...

TGF-β Is Required To Maintain the Pool of Immature Langerhans Cells in the Epidermis

“…5A, 5B). In contrast, similar numbers of Langerin + dermal DCs were present in DC-TbR1 del animals and controls, confirming that Langerin + DC development in the dermis is TGF-b independent, as has recently been demonstrated in TGFb1-deficient mice (35). Moreover, in line with the profound LC low cells were collected from the dermis, and no difference between DC-TbR1 del and nontransgenic littermates was observed (gating strategy as indicated in Supplemental Fig.…”

“…Rather, it supports the crucial role of TGF-b in the induction of Langerin expression by LCs (3). In contrast to LCs, the number of (Langerin + ) dermal DCs in DCTbR1 del animals were similar to wild-type, indicating that Langerin expression and (Langerin + ) DC development in the dermis is TGF-b independent, as has been demonstrated in TGF-b1-deficient mice (35). Furthermore, the immature phenotype of TbR1-deficient dermal DCs in situ suggests that the lack of TGF-b signaling does not affect the maturation and homeostasis of this cutaneous DC population.…”

“…To control for the profound reduction in LC numbers in adult DC-TbR1 del animals, we included Langerin-DTR mice treated with DT on day 214 to selectively deplete LCs, but not Langerin + dermal DCs during the sensitization phase (5,35,36). In response to a low dose of oxazolone, DC-TbR1 del as well as LC-depleted Langerin-DTR mice showed significantly diminished CHS responses as compared with wild-type (Fig.…”

Intradermal immunization in the ear with cholera toxin and its non‐toxic β subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs

“…Although Langerhans cells (LCs) have been shown to be potent APCs in vitro [3], in vivo approaches have produced conflicting data regarding their role in T-cell priming [4,5]. Dermal DCs are also migrating DCs that colonize lymph nodes more rapidly than LCs [6,7], and different roles for skin DC subsets in T-cell priming have been reported [7][8][9]. Skin immunization has yielded controversial data, with some reports supporting a Th2-type response [10,11] and others a Th1-type response [12,13].…”

Dendritic Cells in Distinct Oral Mucosal Tissues Engage Different Mechanisms To Prime CD8+ T Cells

“…Therefore, it is more likely that buccal LCs act as positive regulators during plasmid DNA immunization via a mechanism that is not yet clear. Unfortunately, examining the sole contribution of buccal Ln + iDCs in vivo is impossible in our system, as Lang-DTR mice allow elimination of LCs or both LCs and Ln + iDCs but not Ln + iDCs alone (43). Nevertheless, the ability of Ln + iDCs to present Ag ex vivo and to induce IFN-g secretion by Ag-specific CD8 + T cells suggests that these cells contribute to the overall T cell responses.…”