Abstract
Allergic contact hypersensitivity (CHS) is an inflammatory skin disease mediated by allergen specific T cells. In this study, we investigated the role of transcription factor NFAT1 in the pathogenesis of contact hypersensitivity. NFAT1 knock out (KO) mice spontaneously developed CHS-like skin inflammation in old age. Healthy young NFAT1 KO mice displayed enhanced susceptibility to hapten-induced CHS. Both CD4+ and CD8+ T cells from NFAT1 KO mice displayed hyper-activated properties and produced significantly enhanced levels of inflammatory T helper 1(Th1)/Th17 type cytokines. NFAT1 KO T cells were more resistant to activation induced cell death (AICD), and regulatory T cells derived from these mice showed a partial defect in their suppressor activity. NFAT1 KO T cells displayed a reduced expression of apoptosis associated BCL-2/BH3 family members. Ectopic expression of NFAT1 restored the AICD defect in NFAT1 KO T cells and increased AICD in normal T cells. Recipient Rag2−/− mice transferred with NFAT1 KO T cells showed more severe CHS sensitivity due to a defect in activation induced hapten-reactive T cell apoptosis. Collectively, our results suggest the NFAT1 plays a pivotal role as a genetic switch in CD4+/CD8+ T cell tolerance by regulating AICD process in the T cell mediated skin inflammation.
Highlights
Allergic contact hypersensitivity (CHS) is an inflammatory skin disease mediated by allergen specific T cells
We found that NFAT1 knock out (KO) mice spontaneously developed skin inflammation in old age, and healthy young NFAT1 KO mice were more susceptible to hapten induced allergic contact hypersensitivity
We investigated the possibility that exacerbated pathogenesis of CHS in NFAT1 KO mice is caused by a defect in activation induced cell death (AICD) of hapten reactive pathogenic T cells
Summary
Allergic contact hypersensitivity (CHS) is an inflammatory skin disease mediated by allergen specific T cells. Exposure to the same hapten leads to rapid migration of hapten-specific T cells into inflamed tissues to induce severe inflammation by producing large amounts of pro-inflammatory cytokines and cytotoxic effector molecules[4]. Both CD4+ and CD8+ T cells mediate development and progression of CHS. We found that NFAT1 KO mice spontaneously developed skin inflammation in old age, and healthy young NFAT1 KO mice were more susceptible to hapten induced allergic contact hypersensitivity. Enhanced CHS susceptibility of NFAT1 KO mice was closely related with a functional defect in AICD in both CD4+ and CD8+ T cells due to down-regulation of apoptosis mediators such as FasL and pro-apoptotic Bcl-2/BH3 family proteins. NFAT1 deficient CD4+ and CD8+ T cells produced higher levels of pro-inflammatory and cytolytic molecules, respectively, resulting in exacerbated CHS progression
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