The E-Id Axis Instructs Adaptive Versus Innate Lineage Cell Fate Choice and Instructs Regulatory T Cell Differentiation

Abstract

Immune responses are primarily mediated by adaptive and innate immune cells. Adaptive immune cells, such as T and B cells, evoke antigen-specific responses through the recognition of specific antigens. This antigen-specific recognition relies on the V(D)J recombination of immunoglobulin (Ig) and T cell receptor (TCR) genes mediated by recombination-activating gene (Rag)1 and Rag2 (Rag1/2). In addition, T and B cells employ cell type-specific developmental pathways during their activation processes, and the regulation of these processes is strictly regulated by the transcription factor network. Among these factors, members of the basic helix-loop-helix (bHLH) transcription factor mammalian E protein family, including E12, E47, E2-2, and HEB, orchestrate multiple adaptive immune cell development, while their antagonists, Id proteins (Id1-4), function as negative regulators. It is well established that a majority of T and B cell developmental trajectories are regulated by the transcriptional balance between E and Id proteins (the E-Id axis). E2A is critically required not only for B cell but also for T cell lineage commitment, whereas Id2 and Id3 enforce the maintenance of naïve T cells and naïve regulatory T (Treg) cells. Here, we review the current knowledge of E- and Id-protein function in T cell lineage commitment and Treg cell differentiation.

Keywords: E-Id axis; Rag gene expression; T cell versus ILCs; T-lineage commitment; Treg differentiation.

Figure 1

Model of adaptive and innate lymphocytes lineages mediated by the E-Id axis. The magnitude of E protein transcriptional activity determines the lineage commitments of adaptive versus innate lymphocytes. Following this process, an ensemble of TFs specific for each lineages validates lineage-specific gene expression program, along with E proteins in T and B cells. This figure was created with BioRender.com.

Figure 2

Regulation of Rag gene locus by E2A and cis-regulatory elements. E2A binding to the specific enhancer (R-TEn and R2B) and R1pro regions induces the genome conformation changes to form adaptive lymphocyte-specific SE through the recruitment of P300, TET, and NIPBL-cohesin complex (left; developing T and B cells). In contrast, Id2 prevents E2A/E proteins from binding to these regulatory regions, leading to the insulator formation to sequester the Rag genes in repressive chromatin compartment in innate immune cells (right; macrophage etc). This figure was created with BioRender.com.

Figure 3

The roles of Id2 and Id3 in Treg cell differentiation into subsets of effector Treg cells. Id2 and Id3 enforce the naïve state of Treg cells, especially in T_FR cells. A regulatory switch of Id3 to Id2 plays a role in TR-Treg cell differentiation and function. This figure was created with BioRender.com.