NFATc1 Fosters Allergic Contact Dermatitis Responses by Enhancing the Induction of IL-17-Producing CD8 Cells.

A plethora of data supports a major role of CD4+ and CD8+ T lymphocytes for the initiation, progression, and maintenance of allergic contact dermatitis. However, in-depth understanding of the molecular mechanisms is still limited. NFATc1 plays an essential role in T-cell activation. We therefore investigated its impact on contact hypersensitivity, the mouse model for allergic contact dermatitis. The contact hypersensitivity response to 2,4,6-trinitrochlorobenzene was diminished in Nfatc1fl/flxCd4-cre mice (Nfatc1-/-) compared with that in wild-type mice and associated with a lower percentage of IL-17-producing CD8+ T (Tc17) cells in both inflamed skin and draining lymph nodes. In vitro Tc17 polarization assays revealed that Nfatc1-/- CD8+ T cells have a reduced capacity to polarize into Tc17 cells. Applying single-cell RNA sequencing, we realized that NFATc1 controls the T-cell differentiation fate. In the absence of NFATc1, CD8+ T cells favor the development of IFN-γ-secreting CD8+ T (Tc1) lymphocytes, whereas in its presence, they turn into Tc17 cells. Finally, the adoptive transfer of 2,4,6-trinitrochlorobenzene-sensitized wild-type CD8+ T cells restored the contact hypersensitivity response in naïve Nfatc1-/- mice. Our data demonstrate that NFATc1 contributes to the development of Tc17 cells and might present a promising target to alleviate CD8+ T-cell-mediated allergic responses.