Characterization of Langerin-expressing dendritic cell subsets in the normal cornea.

Langerin is a c-type lectin expressed by specific dendritic cell (DC) populations, and it recognizes glycosylated patterns on pathogens such as mycobacteria. It was initially thought that Langerin is expressed only by Langerhans cells (LCs), a unique population of DCs originally identified in the epidermis that have Birbeck granules.1,2 Recently, however, other DC (CD11c+) populations distinct from LCs were also found to express Langerin.3–7 Such (non-LC) Langerin+ DCs include Langerin+ DCs in the dermis,3–5 a subset of CD8a+ DCs in lymphoid tissues,6,7 and distinct populations in tissues of the lung, gut, kidney, and liver.8 Collectively, (non-LC) Langerin+ DCs are mostly CD11blowCD103+, albeit CD11b+CD103low have also been described.8,9 Furthermore, (non-LC) Langerin+ DCs (often referred to elsewhere as CD103+ DCs) have recently become recognized for their proficiency at antigen cross-presentation through major histocompatibility complex (MHC) class I molecules and, thus, are thought to be critical in host defense against viral infection.10 In the skin, (non-LC) dermal Langerin+ DCs differ from LCs in their capacity to prime specific T-cell subsets.11,12 In addition, (non-LC) dermal Langerin+ DCs are crucial in mounting contact hypersensitivity (CHS), whereas LCs in the epidermis have been shown to play a tolerogenic role and thereby to counteract (non-LC) Langerin+ DCs in CHS.13–15 Thus, it is now well recognized that LCs and (non-LC) Langerin+ DCs are crucial in both mounting and regulating immunologic processes. Despite the importance of these cells, characterization of CD11c+ Langerin+ populations in the cornea, an immune-privileged tissue, is poorly defined. It is agreed that the normal cornea is endowed with a significant population of DCs,16–22 though their frequencies and anatomic location within the cornea are a subject of debate. DCs previously described in the stroma18,20 of normal cornea include CD11c+CD11b+ DCs20 and a population of previously implicated plasmacytoid DCs.21 DCs have also been described in the epithelium of the normal cornea17–19; they are CD11c+CD11blow17,19 and are often collectively referred to as LCs. However, it has recently been shown that only a fraction of corneal epithelial DCs actually express Birbeck granules17 or Langerin.22 Furthermore, whether these are all LCs, or whether there are (non-LC) Langerin+ DCs in the cornea, is completely unknown. In the present study, we found by qRT-PCR, immunohistochemistry, and FACS analysis that both the epithelium and the stroma of the normal murine cornea have CD11c+ Langerin+ populations. Furthermore, using genetically modified mice—including muLangerin-eGFP, huLangerin-DTA, and huLangerin-Cre YFP-flox mice13—previously established to study Langerin+ CD11c+ cells in the skin, we found that the CD11c+ Langerin+ population in the corneal epithelium consists mostly of LCs, whereas those in the corneal stroma were mostly (non-LC) Langerin+ DCs. Thus, such characterizations of CD11c+ Langerin+ subsets in the cornea will permit future work in addressing their role in the immunopathogenesis of clinical conditions such as autoimmune dry eye, allergic conjunctivitis, and corneal transplant rejection.