Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 23, Pages 12980-12990Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1917479117
Keywords
Langerhans cells; aryl hydrocarbon receptor; epicutaneous protein sensitization; Tr1; Th2
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Funding
- Taiwan's Ministry of Science and Technology [MOST 1052314-B-010-054-MY3, 108-2314-B-010-045-MY3, 1072314-B-182A-082-MY3]
- Chang Gung Memorial Foundation [CMRPG8K0291, CMRPG8I0361]
- Kaohsiung Veterans General Hospital [VGHKS108-139]
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The aryl hydrocarbon receptor (AhR) represents an environmental sensor regulating immune responses. In the skin, AhR is expressed in several cell types, including keratinocytes, epidermal Langerhans cells (LC), and dermal dendritic cells (DC). The mechanisms how AhR activates or inhibits cutaneous immune responses remain controversial, owing to differences in the cell-specific functions of AhR and the different activating ligands. Therefore, we sought to investigate the role of AhR in LC and langerin+ and negative DC in the skin. To this aim, we generated Langerinspecific and CD11c-specific knockout ((-/-)) mice lacking AhR, respectively, in LC and Langerin(+) dermal DC and in all CD11c+ cells. These were then tested in an epicutaneous protein (ovalbumin, Ova) sensitization model. Immunofluorescence microscopy and flow cytometry revealed that Langerin-AhR(-/-) but not CD11cAhR(-/-) mice harbored a decreased number of LC with fewer and stunted dendrites in the epidermis as well as a decreased number of LC in skin-draining lymph nodes (LN). Moreover, in the absence of AhR, we detected an enhanced T helper type-2 (Th2) [increased interleukin 5 (IL-5) and interleukin 13 (IL-13)] and T regulatory type-1 (Tr1) (IL-10) response when LN cells were challenged with Ova in vitro, though the number of regulatory T cells (Treg) in the LN remained comparable. Langerin-AhR(-/-) mice also exhibited increased blood levels of Ova-specific immunoglobulin E (IgE). In conclusion, deletion of AhR in langerin-expressing cells diminishes the number and activation of LC, while enhancing Th2 and Tr1 responses upon epicutaneous protein sensitization.
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