NFATc1 drives allergic contact dermatitis reponses by controlling 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 underlying molecular mechanisms is still limited. NFATc1 , a central component of the Ca++-Calcineurin-NFAT-signalling network, 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 Nfatc1fl/flxCd4-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)-g-secreting CD8+ T (Tc1) lymphocytes while in its presence they turn into Tc17 cells. Finally, we showed the adoptive transfer of TNCB-sensitized WT CD8+T cells rescued tThe CHS response could be rescued in naïve Nfatc1-/-mice by adoptive transfer of TNCB-sensitized WT CD8+T cells. Our data demonstrate that NFATc1 acts as a molecular switch controllcontrolsing the development of Tc17 cells and can be used as a target to alleviate surveilling CD8+T cell-mediated CHS responses. C57/B6N WT mice and mice carrying NFATc1 deficiency in T cells through Cre-Lox system (Nfatc1f/f×Cd4-Cre) were used in the experiment. CD8+ T cells from both of these mice were used for the Tc17 (CD8+IL17+) polarization which followed by single cell RNA sequencing of these Tc17 cells. WT mice were the control group and NFATc1 deficient mice were the experimental group.