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Immunol."],"abstract":"<jats:p>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 \u201cClutch\u201d model of differentiation. In this model, Id3 upregulation in response to TCR signaling acts as a clutch that stops E protein activity (\u201cclutch in\u201d) long enough to allow shifting of the genomic landscape into a different \u201cgear\u201d, resulting in accessibility to different E protein target genes once Id3 decreases (\u201cclutch out\u201d) 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.<\/jats:p>","DOI":"10.3389\/fimmu.2022.956156","type":"journal-article","created":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T04:37:08Z","timestamp":1659415028000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation"],"prefix":"10.3389","volume":"13","author":[{"given":"Michele 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