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 (ACD). 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 (CHS), the mouse model for ACD. The CHS response to 2,4,6-trinitrochlorobenzene (TNCB) was diminished in Nfatc1xCd4-cre mice (Nfatc1) as compared to wild-type (WT) animals and associated with a lower percentage of interleukin (IL) 17-producing CD8 T (Tc17) cells in both inflamed skin and draining lymph nodes (dLN). 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 favour the development of Interferon (IFN)-γ-secreting CD8 T (Tc1) lymphocytes while in its presence they turn into Tc17 cells. Finally, the adoptive transfer of TNCB-sensitized WT CD8 T cells restored the CHS response in naïve Nfatc1mice. 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.