This construct is simplistic on multiple levels and ignores or underemphasizes the involvement and importance of many cells (including keratinocytes, mast cells, NK cells, and B cells) and an array of proinflammatory and/or immunoregulatory cytokines and chemokines and associated downstream signaling molecules as well as other soluble mediators, including complement proteins and other proteases. Recently recognized phenotypic heterogeneity of skin DCs was also not taken into account.
Epidermal Langerhans cells (LCs) represent the most extensively studied skin DC subpopulation, and all DCs in unperturbed epidermis are LCs. In contrast, there are multiple DC subpopulations in mammalian dermis, and these cells are distinct from LCs (
4–
6). Experimentally, LCs can be differentiated from dermal DCs based on their expression of the C-type lectin Langerin and several surface markers, relative radioresistance, slow turnover, and TGF-β dependence. Complicating these lineage definitions, a small subpopulation of dermal DCs in mice that are not related to LCs expresses Langerin (
4–
6).
In the contact hypersensitivity paradigm described above, it was presumed that, because of their location in the outermost layer of skin (epidermis) and their potency as APCs in vitro and after adoptive transfer in vivo, LCs actively participated in generation of effector immune responses. Development of transgenic mice that were LC deficient by three separate groups (
7–
9) allowed formal testing of this hypothesis. Surprisingly, none of the initial experiments indicated that LCs were absolutely required during sensitization or elicitation phases of contact sensitivity reactions. Two of the models involved depletion of Langerin-expressing DCs and LCs (
7,
8), and the modest decrements in inflammation observed can now be attributed to involvement of dermal DCs in T cell priming to contact allergens (reviewed in ref.
10). In the other model (in which only LCs were absent), contact sensitivity to DNFB was actually increased approximately 2-fold (
9). In a follow-up study, attenuation of DNFB-induced responses by LCs required that LCs express MHC class II antigens and produce IL-10, the former implying a requisite physical interaction between LCs and CD4
+ T cells (
11).
Judicious study of mice deficient in LCs and Langerin-expressing dermal DCs has subsequently resulted in a number of important insights into cutaneous DC function. The essential involvement of LCs in contact sensitivity reactions (
10), skin graft rejection (
12), reactivity to skin self antigens (
13), graft-versus-host disease (
14), several skin infections (including herpes simplex, ref.
15; leishmaniasis, ref.
16; and candidiasis, ref.
17) and antibody production in response to cutaneous antigen exposure (
18,
19) has been excluded, and instead, an immunomodulatory role for LCs has emerged. In addition to the initial report that documented enhanced contact sensitivity responses in mice lacking only LCs (
10), subsequent studies have implicated LCs in tolerance to minor histocompatibility antigens (
12), generation of Th17 cells (
17), attenuation of antiparasite responses (
16), and regulation of isotype utilization in antibody responses (
18,
19). In this issue of the
JCI, Gomez de Agüero and coworkers extend these observations, convincingly implicating LCs in tolerance to a contact allergen (
20).
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