Langerhans cells and the cells of Langerhans cell histiocytosis do not express DC-SIGN

Geissmann and colleagues recently reported that cells of Langerhans cell histiocytosis (LCH) in osseous and/or chronic lesions have an immature dendritic cell phenotype.1 In addition to CD1a, LCH cells in all 25 cases examined expressed Langerin, a recently described C-type lectin that appears to be restricted entirely to Langerhans cells.2 

An increasing number of dendritic cell lectins, such as dendritic cell–specific ICAM-grabbing nonintegrin (DC-SIGN), dendritic cell immunoreceptor (DCIR), DEC-205, and CD23, are now recognized.3 We consider it important to determine whether these lectins are expressed on similar, overlapping, or mutually exclusive dendritic cell subsets, as such information may suggest the biological roles of the individual lectins. Our recent work has focused on DC-SIGN (manuscript submitted and Soilleux et al4), which has 32% sequence identity at the amino acid level to Langerin across the carbohydrate recognition domain. DC-SIGN has the capacity to bind the HIV surface molecule glycoprotein 120 in an inhibitable manner by mannose,5,6 as well as the lymphocytic surface-expressed molecule ICAM-3,7 and the endothelial surface molecule ICAM-2.8 Langerin also possesses the critical mannose binding motif seen in DC-SIGN. It has not yet been determined whether HIV may interact with Langerin in a manner analogous to its interaction with DC-SIGN.

We have recently demonstrated that DC-SIGN is expressed by cells with an immature dendritic cell phenotype (manuscript submitted) similar to that described by Geissmann et al1 in LCH cells. In our study, the DC-SIGN⁺ cells were CD14^lowHLA-DR^+/low CD68⁺8100^+/− and only rarely expressed dendritic cell activation markers such as CD83, CD86, and cmrf-44 (manuscript submitted). Moreover, the DC-SIGN⁺ cells were consistently negative for CDla (manuscript submitted). Cells matured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-α (TNF-α), transforming growth factor β (TGF-β), stem cell factor (SCF), and flt-3 ligand from CD34⁺lin⁻ peripheral blood cell precursors, to give a Langerhans cell phenotype,9 showed no evidence of DC-SIGN expression by reverse transcriptase–polymerase chain reaction (RT-PCR).4 Dendritic cells matured from peripheral blood monocytes in the presence of GM-CSF and interleukin-4 (IL-4) and could be shown to express DC-SIGN both by RT-PCR and fluorescence-activated cell sorting analysis (manuscript submitted and Soilleux et al4).

In view of the findings of Geissmann et al,1 we have extended our analysis of the expression of DC-SIGN in relation to CDla on dendritic cells by examining 4 specimens of normal skin and 8 specimens of LCH obtained from the Department of Histopathology, Addenbrooke's Hospital, Cambridge, United Kingdom. Two of the LCH cases were from the retro-orbital region, 3 were from bone, and 1 was from skin. We performed immunohistochemistry on serial sections using our rabbit polyclonal anti–DC-SIGN antibody (manuscript submitted) and mouse monoclonal anti-CDla (Novacastra, Newcastle-upon-Tyne, United Kingdom).

In all 4 specimens of normal skin, the CD1a⁺ cells in the epidermis and at the dermo-epidermal junction did not express DC-SIGN, whereas CDla⁻ dendritic cells present within the dermis did (Figure 1A-B). In all 8 specimens of LCH, the CDla⁺ cells within the infiltrate were negative for DC-SIGN, though occasional DC-SIGN–expressing cells could be seen in surrounding tissue acting as a useful internal positive control (Figure 1C-D). Our data are in accordance with previous results suggesting that expression of DC-SIGN and expression of the Langerhans cell–restricted molecule CDla are mutually exclusive (manuscript submitted, Soilleux et al,4 and Geijtenbeek et al7). Our findings, when considered with those of Geissmann et al, indicate that DC-SIGN is only expressed on a subset of dendritic cells with an immature phenotype. Given the very similar expression patterns of Langerin and CD1a,1 our data suggest that DC-SIGN and Langerin are expressed by mutually exclusive dendritic cell subsets. Whether there are functional differences between Langerhans cells and DC-SIGN⁺ dendritic cells remains to be determined. The 2 novel C-type lectins, Langerin and DC-SIGN, may have analogous properties on separate dendritic cell subsets with respect to, for example, their capacity to bind T lymphocytes and lentiviruses.