| First Author | Shim JA | Year | 2023 |
| Journal | Cell Commun Signal | Volume | 21 |
| Issue | 1 | Pages | 309 |
| PubMed ID | 37904191 | Mgi Jnum | J:358070 |
| Mgi Id | MGI:7545912 | Doi | 10.1186/s12964-023-01326-7 |
| Citation | Shim JA, et al. (2023) NFAT1 and NFkappaB regulates expression of the common gamma-chain cytokine receptor in activated T cells. Cell Commun Signal 21(1):309 |
| abstractText | INTRODUCTION: Cytokines of the common gamma chain (gammac) family are critical for the development, differentiation, and survival of T lineage cells. Cytokines play key roles in immunodeficiencies, autoimmune diseases, allergies, and cancer. Although gammac is considered an assistant receptor to transmit cytokine signals and is an indispensable receptor in the immune system, its regulatory mechanism is not yet well understood. OBJECTIVE: This study focused on the molecular mechanisms that gammac expression in T cells is regulated under T cell receptor (TCR) stimulation. METHODS: The gammac expression in TCR-stimulated T cells was determined by flow cytometry, western blot and quantitative RT-PCR. The regulatory mechanism of gammac expression in activated T cells was examined by promoter-luciferase assay and chromatin immunoprecipitation assays. NFAT1 and NFkappaB deficient cells generated using CRISPR-Cas9 and specific inhibitors were used to examine their role in regulation of gammac expression. Specific binding motif was confirmed by gammac promotor mutant cells generated using CRISPR-Cas9. IL-7TggammacTg mice were used to examine regulatory role of gammac in cytokine signaling. RESULTS: We found that activated T cells significantly upregulated gammac expression, wherein NFAT1 and NFkappaB were key in transcriptional upregulation via T cell receptor stimulation. Also, we identified the functional binding site of the gammac promoter and the synergistic effect of NFAT1 and NFkappaB in the regulation of gammac expression. Increased gammac expression inhibited IL-7 signaling and rescued lymphoproliferative disorder in an IL-7Tg animal model, providing novel insights into T cell homeostasis. CONCLUSION: Our results indicate functional cooperation between NFAT1 and NFkappaB in upregulating gammac expression in activated T cells. As gammac expression also regulates gammac cytokine responsiveness, our study suggests that gammac expression should be considered as one of the regulators in gammac cytokine signaling and the development of T cell immunotherapies. Video Abstract. |
