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

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.

The transcription factor E2A activates multiple enhancers that drive Rag expression in developing T and B cells.

Cell type-specific gene expression is driven by the interplay between lineage-specific transcription factors and cis-regulatory elements to which they bind. Adaptive immunity relies on RAG-mediated assembly of T cell receptor (TCR) and immunoglobulin (Ig) genes. Although Rag1 and Rag2 expression is largely restricted to adaptive lymphoid lineage cells, it remains unclear how Rag gene expression is regulated in a cell lineage-specific manner. Here, we identified three distinct cis-regulatory elements, a T cell lineage-specific enhancer (R-TEn) and the two B cell-specific elements, R1B and R2B By generating mice lacking either R-TEn or R1B and R2B, we demonstrate that these distinct sets of regulatory elements drive the expression of Rag genes in developing T and B cells. What these elements have in common is their ability to bind the transcription factor E2A. By generating a mouse strain that carries a mutation within the E2A binding site of R-TEn, we demonstrate that recruitment of E2A to this site is essential for orchestrating changes in chromatin conformation that drive expression of Rag genes in T cells. By mapping cis-regulatory elements and generating multiple mouse strains lacking distinct enhancer elements, we demonstrate expression of Rag genes in developing T and B cells to be driven by distinct sets of E2A-dependent cis-regulatory modules.