Department of Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada.
Department of Immunology, University of Toronto, Toronto, ON, Canada.
Front Immunol. 2022 Aug 2;13:956156. doi: 10.3389/fimmu.2022.956156. eCollection 2022.
Shifting levels of E proteins and Id factors are pivotal in T cell commitment and differentiation, both in the thymus and in the periphery. Id2 and Id3 are two different factors that prevent E proteins from binding to their target gene cis-regulatory sequences and inducing gene expression. Although they use the same mechanism to suppress E protein activity, Id2 and Id3 play very different roles in T cell development and CD4 T cell differentiation. Id2 imposes an irreversible choice in early T cell precursors between innate and adaptive lineages, which can be thought of as a railway switch that directs T cells down one path or another. By contrast, Id3 acts in a transient fashion downstream of extracellular signals such as T cell receptor (TCR) signaling. TCR-dependent Id3 upregulation results in the dislodging of E proteins from their target sites while chromatin remodeling occurs. After the cessation of Id3 expression, E proteins can reassemble in the context of a new genomic landscape and molecular context that allows induction of different E protein target genes. To describe this mode of action, we have developed the "Clutch" model of differentiation. In this model, Id3 upregulation in response to TCR signaling acts as a clutch that stops E protein activity ("clutch in") long enough to allow shifting of the genomic landscape into a different "gear", resulting in accessibility to different E protein target genes once Id3 decreases ("clutch out") and E proteins can form new complexes on the DNA. While TCR signal strength and cytokine signaling play a role in both peripheral and thymic lineage decisions, the remodeling of chromatin and E protein target genes appears to be more heavily influenced by the cytokine milieu in the periphery, whereas the outcome of Id3 activity during T cell development in the thymus appears to depend more on the TCR signal strength. Thus, while the Clutch model applies to both CD4 T cell differentiation and T cell developmental transitions within the thymus, changes in chromatin accessibility are modulated by biased inputs in these different environments. New emerging technologies should enable a better understanding of the molecular events that happen during these transitions, and how they fit into the gene regulatory networks that drive T cell development and differentiation.
E 蛋白和 Id 因子的水平变化在 T 细胞的定向和分化中起着关键作用，无论是在胸腺还是在外周。Id2 和 Id3 是两种不同的因子，它们阻止 E 蛋白与其靶基因顺式调控序列结合并诱导基因表达。虽然它们使用相同的机制来抑制 E 蛋白的活性，但 Id2 和 Id3 在 T 细胞发育和 CD4 T 细胞分化中发挥着非常不同的作用。Id2 在早期 T 细胞前体中不可逆地选择固有和适应性谱系，可以将其视为一个铁路开关，引导 T 细胞走一条或另一条路。相比之下，Id3 在细胞外信号（如 T 细胞受体 (TCR) 信号）下游以短暂的方式发挥作用。TCR 依赖性 Id3 的上调导致 E 蛋白从其靶位点上脱离，同时发生染色质重塑。Id3 表达停止后，E 蛋白可以在新的基因组景观和分子环境中重新组装，允许诱导不同的 E 蛋白靶基因。为了描述这种作用模式，我们提出了分化的“离合器”模型。在这个模型中，TCR 信号响应导致的 Id3 上调充当了离合器，使 E 蛋白的活性“离合器合上”（“clutch in”）足够长的时间，以使基因组景观转变到不同的“档位”，从而在 Id3 减少时（“clutch out”），E 蛋白可以在 DNA 上形成新的复合物，并获得不同的 E 蛋白靶基因的可及性。虽然 TCR 信号强度和细胞因子信号在周围和胸腺谱系决定中都起着作用，但染色质重塑和 E 蛋白靶基因似乎更多地受到周围细胞因子环境的影响，而在胸腺中 T 细胞发育过程中 Id3 活性的结果似乎更多地取决于 TCR 信号强度。因此，虽然离合器模型适用于 CD4 T 细胞分化和胸腺内 T 细胞发育过渡，但染色质可及性的变化受到这些不同环境中偏向输入的调节。新兴技术应该能够更好地理解这些过渡过程中发生的分子事件，以及它们如何适应驱动 T 细胞发育和分化的基因调控网络。
