Langerhans cells dampen contact hypersensitivity

July 1, 2006

New Haven, Conn. - Epidermal Langerhans cells (LCs), long thought to play a role in the initiation of contact hypersensitivity (CHS), appear to actually have quite the opposite function in the development of CHS responses, according to a report recently published in Immunity.

New Haven, Conn. - Epidermal Langerhans cells (LCs), long thought to play a role in the initiation of contact hypersensitivity (CHS), appear to actually have quite the opposite function in the development of CHS responses, according to a report recently published in Immunity.

Hoping to uncover the role of LCs in skin immunity, researchers developed a transgenic mouse that lacked LCs. They then evaluated CHS responses in those mice.

"Unexpectedly, instead of a decreased immune response, we found a reproducible and significant increase" in CHS in the LCs-deficient mice, says Daniel H. Kaplan, M.D., Ph.D., assistant professor of dermatology at Yale University School of Medicine in New Haven, Conn.

LCs are a subset of dendritic cells that are localized to the epidermis. This distribution positions LCs to be the first antigen-presenting cells (APC) to interact with skin-borne pathogens.

Under some conditions, LCs have been shown to process antigens, migrate to draining lymph nodes and present antigens to T cells. However, data on the exact role of LCs in initiation of immune responses are contradictory.

Previous research showed LCs to be important in the development of CHS. For example, treating skin with ultraviolet light before priming with the CHS antigen hapten was found to cause removal of LCs from the skin and the CHS response did not develop.

Other immunological model systems, however, have shown that LCs are not involved in the development of CHS responses.

Transgenic mice illuminate role of LCs

In order to sort out the role of LCs in skin immunity, Dr. Kaplan and colleagues developed transgenic mice expressing attenuated diphtheria toxin from birth exclusively in LCs.

To generate this cell type-specific expression, investigators inserted the diphtheria toxin sequence into the human LC-specific gene, Langerin, which was obtained from a bacterial artificial chromosome.

Two founder animals exhibited a complete lack of epidermal LCs. Dermal dendritic cells were preserved, as were the dendritic epidermal T cells and the dendritic cell subsets in secondary lymphoid tissues.

Of particular interest is the role of LCs in initiating CHS responses. Dr. Kaplan and colleagues therefore evaluated differences in the CHS response resulting from an absence of LCs.

They epicutaneously applied hapten to the shaved but intact skin of LC-deficient (Langerin-DTA) mice and litter-mate controls. After five days, investigators rechallenged with hapten on the ear skin and measured CHS by the degree of ear swelling after 24 hours. This classic CHS model is thought to mimic natural exposure to environmental antigens as it does not require disruption of the epidermis or stratum corneum.

Although the classical models of LC function would predict an impaired CHS in the absence of LCs, LC-deficient mice were still able to mount a CHS response and actually demonstrated twice as much ear swelling as their litter-mate controls.

"This is a major finding from this study - that mice that lack LCs still develop contact dermatitis," Dr. Kaplan tells Dermatology Times. "This shows that LCs are not required for the development of cutaneous immune responses. Moreover, mice lacking LCs developed much more severe contact dermatitis than their wild-type counterparts. This was unexpected and demonstrates that LCs, in fact, regulate cutaneous immune responses."

LCs prime CHS response

A series of adoptive transfer experiments revealed that LCs appear to act during the priming phase and not during the effector phase of the immune response.

"We noted an almost twofold increase in ear swelling in wild-type animals that received primed lymph node cells from Langerin DTA-mice compared with cells from litter-mate controls," Dr. Kaplan says.

On the other hand, lymph node cells that were primed in wild-type animals induced a similar degree of ear swelling whether they were transferred to wild-type or LC-deficient mice.

Investigators are currently testing other cutaneous responses and investigating the role of LCs in several animal disease models.