Molecular and Cellular Immunoregulation Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States.
Front Immunol. 2023 Jun 28;14:1186580. doi: 10.3389/fimmu.2023.1186580. eCollection 2023.
T-bet-expressing Th17 (T-betRORγt) cells are associated with the induction of pathology during experimental autoimmune encephalomyelitis (EAE) and the encephalitic nature of these Th17 cells can be explained by their ability to produce GM-CSF. However, the upstream regulatory mechanisms that control (gene encoding GM-CSF) expression are still unclear. In this study, we found that Th17 cells dynamically expressed GATA3, the master transcription factor for Th2 cell differentiation, during their differentiation both and . Early deletion of in three complimentary conditional knockout models by Cre-ERT2, and , respectively, limited the pathogenicity of Th17 cells during EAE, which was correlated with a defect in generating pathogenic T-bet-expressing Th17 cells. These results indicate that early GATA3-dependent gene regulation is critically required to generate a encephalitogenic Th17 response. Furthermore, a late deletion of via Cre-ERT2 in the adoptive transfer EAE model resulted in a cell intrinsic failure to induce EAE symptoms which was correlated with a substantial reduction in GM-CSF production without affecting the generation and/or maintenance of T-bet-expressing Th17 cells. RNA-Seq analysis of sufficient and -deficient CNS-infiltrating CD4 effector T cells from mixed congenic co-transfer recipient mice revealed an important, cell-intrinsic, function of GATA3 in regulating the expression of , , and . Thus, our data highlights a novel role for GATA3 in promoting and maintaining the pathogenicity of T-bet-expressing Th17 cells in EAE, via putative regulation of Egr2, Bhlhe40, and GM-CSF expression.
T 细胞特异性转录因子（T-bet）表达的 Th17（T-betRORγt）细胞与实验性自身免疫性脑脊髓炎（EAE）期间的病理学诱导有关，这些 Th17 细胞的脑炎性质可以通过它们产生 GM-CSF 的能力来解释。然而，控制（GM-CSF 基因编码）表达的上游调节机制仍不清楚。在这项研究中，我们发现 Th17 细胞在分化过程中动态表达 GATA3，GATA3 是 Th2 细胞分化的主转录因子，无论是在体内还是体外。通过 Cre-ERT2 分别在三个互补的条件性敲除模型中早期删除，限制了 Th17 细胞在 EAE 中的致病性，这与产生致病性 T-bet 表达 Th17 细胞的缺陷相关。这些结果表明，早期的 GATA3 依赖性基因调控对于产生致脑炎的 Th17 反应至关重要。此外，通过 Cre-ERT2 在过继转移 EAE 模型中晚期删除导致细胞内在的诱导 EAE 症状的失败，这与 GM-CSF 产生的大量减少相关，而不影响 T-bet 表达 Th17 细胞的产生和/或维持。从混合同基因共转移受体小鼠的中枢神经系统浸润 CD4 效应 T 细胞中进行充分和 - 缺陷的 RNA-Seq 分析揭示了 GATA3 在调节表达中的一个重要的、细胞内在的作用，包括，，和。因此，我们的数据强调了 GATA3 通过可能调节 Egr2、Bhlhe40 和 GM-CSF 表达，在 EAE 中促进和维持 T-bet 表达的 Th17 细胞的致病性方面的新作用。
