Helix-Loop-Helix Proteins in Adaptive Immune Development

Abstract

The E/ID protein axis is instrumental for defining the developmental progression and functions of hematopoietic cells. The E proteins are dimeric transcription factors that activate gene expression programs and coordinate changes in chromatin organization. Id proteins are antagonists of E protein activity. Relative levels of E/Id proteins are modulated throughout hematopoietic development to enable the progression of hematopoietic stem cells into multiple adaptive and innate immune lineages including natural killer cells, B cells and T cells. In early progenitors, the E proteins promote commitment to the T and B cell lineages by orchestrating lineage specific programs of gene expression and regulating VDJ recombination of antigen receptor loci. In mature B cells, the E/Id protein axis functions to promote class switch recombination and somatic hypermutation. E protein activity further regulates differentiation into distinct CD4+ and CD8+ T cells subsets and instructs mature T cell immune responses. In this review, we discuss how the E/Id proteins define the adaptive immune system lineages, focusing on their role in directing developmental gene programs.

Keywords: B cell development; E proteins; HLH; Id proteins; T cell development; VDJ recombination; hematopoiesis; lymphopoiesis.

Figure 1

Lymphopoiesis is directed by E protein activity in early stem cells. The role of E and Id proteins in early progenitors giving rise to B and T cells is depicted in the bone marrow. Protein factors that support stem cell maintenance or self-renewal are indicated adjacent to each cell, and bolded arrows represent lineage differentiation (Created with BioRender.com).

Figure 2

B cell fate and differentiation is directed by E protein activity. The role of E proteins and their antagonists in B cell development is shown in the bone marrow and lymphoid organs. Protein factors supportive of differentiation or cell maintenance are indicated in black font next to the arrows or adjacent to the cell respectively. Protein factors with repressive functions are indicated in red font (Created with BioRender.com).

Figure 3

Enhancer activation by E2A drives IgK recombination.The IgK locus is poised for recombination in pro-B cells—when E2A is bound to V_K genes, V_K regions have acetylated histone marks, and the locus is already contracted, with iE_K making extensive contacts with the V_K region. Activation of the locus coincides with E2A activation of the IgK enhancers. Pre-BCR signaling and IL-7/STAT5 attenuation render the iE_K and 3’E_K enhancers insensitive to STAT5. E2A occupancy at the enhancers increases, and the Tet proteins are recruited to 3’E_K where they demethylate CpG residues. The now accessible 3’E_K enhancer forms extensive contacts with the V_K region.

Figure 4

T cell fate and differentiation is directed by E protein activity. The role of E proteins and their antagonists in T cell development is shown in the thymus and lymphoid organs. Protein factors supportive of differentiation or cell maintenance are indicated in black font next to the arrows or adjacent to the cell respectively. Protein factors with repressive functions are indicated in red font (Created with BioRender.com).

Figure 5

HEB prolongs survival of DP thymocytes and rearrangements of distal V_α and J_α gene segments. Rearrangement of the TCRα locus proceeds by a deletional mechanism, in which the more proximal gene segments rearrange first. Cells that undergo productive rearrangements that pass positive selection mature into CD4+ and CD8+ mature T cells. Cells with unproductive rearrangements undergo secondary rearrangements, until the cells either produce a productive TCRα allele or undergo cell death. HEB, along with TCF-1, promotes rearrangements of more distal TCRα genes by prolonging cell survival during this process. HEB is crucial for the rearrangement of distal TCRα genes, production of a diverse αβ T cell repertoire, and generation of iNKT cells expressing an invariant TCRα protein composed of the distally located V_α14 and J_α18 genes.