Epidermal Langerhans Cell-Deficient Mice Develop Enhanced Contact Hypersensitivity

Abstract

Epidermal Langerhans cells (LCs), a distinct skin-resident dendritic cell population, acquire antigen in the skin and migrate to draining lymph nodes where they are thought to initiate adaptive immune responses. To examine the functional requirement of LCs in skin immunity, we generated BAC transgenic mice in which the regulatory elements from human Langerin were used to drive expression of diphtheria toxin. The resulting mice have a constitutive and durable absence of epidermal LCs but are otherwise intact. Unexpectedly, we found that contact hypersensitivity (CHS) was amplified rather than abrogated in the absence of LCs. Moreover, we showed that LCs act during the priming and not the effector phase. Thus, LCs not only were dispensable for CHS, but they served to regulate the response, a previously unappreciated function.

Insights into Langerhans cell function from Langerhans cell ablation models

“…In contrast, Dutch Langerin-DTR-EGFP mice treated with DT 3 days prior to sensitization developed diminished but not absent CHS in response to a standard dose of another hapten, trinitrochlorobenzene, suggesting that LC are required for optimal initiation of CHS responses [29]. Finally, the American Langerin-DTA mice, constitutively lacking LC, developed enhanced CHS responses compared with littermate controls to both DNFB and a third hapten, oxazalone [31]. This was interpreted as showing that LC have a regulatory role and limit CHS responses.…”

“…Our third (American) group used an alternative approach and generated bacterial artificial chromosome (BAC)-transgenic mice by inserting DTA (not DTR) into the 3 0 -untranslated region of the langerin gene contained within a 70-kb fragment of human genomic BAC DNA [31]. Since DTA is expressed coordinately with Langerin, the resulting Langerin-DTA (American) mice have a constitutive and durable absence of LC.…”

“…This was interpreted as showing that LC have a regulatory role and limit CHS responses. The altered CHS responses observed in the Dutch and American mice were antigen-specific and required the absence of LC during the sensitization and not challenge phases [30,31,35]. Thus, rather than establishing a precise role for LC, there were divergent results for CHS (no change, decreased and increased) in three independent models of LC deficiency.…”

“…Repopulation of the depleted epidermis is slow with patches of LC starting to reappear only at 2-4 wk post-DT injection. Although langerin was thought to be expressed only by epidermal LC, a subset of CD8a 1 DC found throughout the secondary lymphoid tissues (LN, spleen and thymus) also express Langerin and are ablated after DT administration [30].Our third (American) group used an alternative approach and generated bacterial artificial chromosome (BAC)-transgenic mice by inserting DTA (not DTR) into the 3 0 -untranslated region of the langerin gene contained within a 70-kb fragment of human genomic BAC DNA [31]. Since DTA is expressed coordinately with Langerin, the resulting Langerin-DTA (American) mice have a constitutive and durable absence of LC.…”

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

“…Efficient immunosurveillance in the skin is based upon the continuous traffic of cells from the skin to the draining lymph nodes. 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].…”