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The function of E- and id proteins in lymphocyte development

Nature Reviews Immunology volume 1, pages 193–199 (2001)Cite this article

Key Points

  • E-proteins are helix–loop–helix (HLH) transcription factors that are important regulators of lymphocyte development. The mammalian E-proteins are encoded by the E2A, HEB and E2-2 genes.

  • Id proteins act as dominant-negative inhibitors of E-protein function by forming dimers with E-proteins that are unable to bind DNA. There are four mammalian Id proteins, which have been designated Id1–4.

  • E2A proteins are absolutely essential for the initial steps of B-cell differentiation, before irreversible commitment to the B lineage. E2A proteins are also important for the initial stages of T-cell development in the thymus, although some T-cell maturation does occur in an E2A-deficient background.

  • E2A proteins have been shown to regulate the expression of several genes that are important in the initial stages of B- and T-cell development. These include early B-cell factor (EBF) and Pax5 in pro-B cells, the pre-Tα gene in DN thymocytes, and the RAG genes in both lymphocyte lineages.

  • HEB null mice show T-cell developmental defects that are distinct from that of E2A-deficient mice, involving disruption of the DN–DP transition. So, E2A and HEB proteins have at least some unique functions in T-cell differentiation.

  • E2A proteins act as attenuators of thymocyte positive selection. Signals initiated by the crosslinking of the T-cell receptor (TCR) complex and transmitted through the RAS–ERK–MAP kinase pathway act to inhibit E-protein activity, at least in part through an increase in the levels of Id3.

  • Id3 is essential for normal thymocyte positive selection. The effects of an absence of Id3 on positive selection can be suppressed by a deficiency of E2A, showing that E2A and Id3 interact both biochemically and genetically in T-cell development.

  • E2A proteins are essential for maintaining the block in development caused by mutations in genes required for TCRβ rearrangement and expression, such as RAG and scid. Signalling through the pre-TCR complex in double-negative thymocytes acts to inhibit E-protein activity through mechanisms that seem similar to those observed for αβTCR signalling at the double-positive stage.

  • E2A protein activity also seems to affect later stages of B-cell development. The apoptotic effects of transforming growth factor-β on B-cell progenitor cultures are dependent on Id3 and, in activated B cells, E2A is probably necessary for the promotion of isotype switching.

  • Enforced Id expression inhibits the development of lymphoid dendritic cells (DCs). These data imply that other factors act downstream of E-proteins to determine T versus DC fate.

Abstract

Helix–loop–helix proteins are essential factors for lymphocyte development and function. In particular, E-proteins are crucial for commitment of lymphoid progenitors to the B- and T-cell lineages. E-proteins are negatively regulated by the Id class of helix–loop–helix proteins. The Id proteins function as dominant-negative inhibitors of E-proteins by inhibiting their ability to bind DNA. Here, we review the role of E-proteins and their Id protein antagonists in lymphocyte proliferation and developmental progression. In addition, we discuss how E-protein activity and Id gene expression are regulated by T-cell receptor (TCR) and pre-TCR-mediated signalling.

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Figure 1: Schematic model of T-cell and B-cell development.
Figure 2: E- and Id protein structure and function.
Figure 3: Inhibition of E2A by TCR signalling.
Figure 4: Model that outlines the role and regulation of E2A during T-cell development.

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Authors and Affiliations

  1. Division of Biology, 0366, University of California, San Diego, La Jolla, 92093, California, USA

    Isaac Engel & Cornelis Murre

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  1. Isaac Engel
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Correspondence to Cornelis Murre.

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DATABASES

LocusLink

CD4

CD8

CD25

CD44

E2-2

E2A

E12

E47

EBF

Egr1

HEB

Id1–4

MEK1

MEK2

Pax5

RAG1

RAG2

TGF-β

FURTHER INFORMATION

Cornelis Murre's lab

Encyclopedia of Life Sciences

Lymphocyte development

Glossary

ANERGIZED

A state of non-responsiveness to antigen.

SCID MUTANT

A naturally occurring mouse mutant with severe combined immune deficiency, due to an inability to rearrange antigen-receptor chain genes.

SMAD FAMILY

Transcription factors that are activated by TGF-β signalling.

NOTCH SIGNALLING

A signalling system comprising highly conserved transmembrane receptors that regulate cell-fate choice in the development of many cell lineages, including lymphocytes.

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Engel, I., Murre, C. The function of E- and id proteins in lymphocyte development. Nat Rev Immunol 1, 193–199 (2001). https://doi.org/10.1038/35105060

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