Azeem Muhammad, Helal Moutaz, Klein-Hessling Stefan, Serfling Edgar, Goebeler Matthias, Muhammad Khalid, Kerstan Andreas
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany; Department of Molecular Pathology, Institute of Pathology, University of Würzburg, Würzburg, Germany.
Mildred Scheel Early Career Centre (MSNZ) for Cancer Research, University Hospital Würzburg, Würzburg, Germany.
J Invest Dermatol. 2025 Aug;145(8):1995-2006.e5. doi: 10.1016/j.jid.2024.11.014. Epub 2024 Dec 27.
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 Nfatc1xCd4-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.
大量数据支持CD4和CD8 T淋巴细胞在过敏性接触性皮炎的起始、进展和维持中起主要作用。然而，对其分子机制的深入理解仍然有限。NFATc1在T细胞活化中起关键作用。因此，我们研究了它对接触性超敏反应（过敏性接触性皮炎的小鼠模型）的影响。与野生型小鼠相比，Nfatc1xCd4-cre小鼠（Nfatc1）对2,4,6-三硝基氯苯的接触性超敏反应减弱，且在炎症皮肤和引流淋巴结中产生IL-17的CD8 T（Tc17）细胞百分比降低。体外Tc17极化试验表明，Nfatc1 CD8 T细胞极化成为Tc17细胞的能力降低。应用单细胞RNA测序，我们发现NFATc1控制T细胞分化命运。在没有NFATc1的情况下，CD8 T细胞倾向于发育为分泌IFN-γ的CD8 T（Tc1）淋巴细胞，而在有NFATc1的情况下，它们会转变为Tc17细胞。最后，过继转移2,4,6-三硝基氯苯致敏的野生型CD8 T细胞可恢复幼稚Nfatc1小鼠的接触性超敏反应。我们的数据表明，NFATc1有助于Tc17细胞的发育，可能是减轻CD8 T细胞介导的过敏反应的一个有前景的靶点。
