E proteins and the regulation of early lymphocyte development

Abstract

Lymphopoiesis generates mature B, T, and NK lymphocytes from hematopoietic stem cells via a series of increasingly restricted developmental intermediates. The transcriptional networks that regulate these fate choices are composed of both common and lineage-specific components, which combine to create a cellular context that informs the developmental response to external signals. E proteins are an important factor during lymphopoiesis, and E2A in particular is required for normal T- and B-cell development. Although the other E proteins, HEB and E2-2, are expressed during lymphopoiesis and can compensate for some of E2A's activity, E2A proteins have non-redundant functions during early T-cell development and at multiple checkpoints throughout B lymphopoiesis. More recently, a role for E2A has been demonstrated in the generation of lymphoid-primed multipotent progenitors and shown to favor their specification toward lymphoid over myeloid lineages. This review summarizes both our current understanding of the wide-ranging functions of E proteins during the development of adaptive lymphocytes and the novel functions of E2A in orchestrating a lymphoid-biased cellular context in early multipotent progenitors.

Fig. 1. Mechanism of lymphocyte specification and commitment

E2A collaborates with multiple factors to promote lymphoid priming, which is the low abundance expression of multiple lymphocyte-associated genes. The complement of genes induced in individual LMPPs may differ depending on the concentration of each of the transcriptional regulators leading to a heterogenous population. Heterogeneous lymphoid priming leads to the expression of multiple receptors and signaling molecules that allows variation in the response to extrinsic signals. These signaling pathways (IL-7R or Notch signaling) can induce transcription factors that collaborate with E proteins to induce novel transcriptional regulatory networks required for B or T lymphopoiesis. Commitment to the adaptive or innate lymphoid pathways involves activation of repression of essential regulators of the alterative fate.

Fig. 2. E47 is expressed at similar levels in all DN thymocyte subsets

(A) Total thymocytes from C57Bl/6 mice were stained with a lineage cocktail including antibodies to CD8, CD3, TCRβ, TCRγ, CD11b, CD11c, Gr1, NK1.1, and B220 as well as CD44, CD25 and E47 or control IgG. CD44 and CD25 expression are shown on Lineage negative thymocytes. B) Histogram showing E47 staining in ETPs (Lin⁻CD44⁺CD35⁻), DN2s (Lin⁻CD44⁺CD25⁺), DN3s (Lin⁻CD44⁻CD25⁺), and DN4s (Lin⁻CD44⁻CD25⁻). Isotype control staining is shown in gray.

Fig. 3. Regulatory Networks in Lymphopoiesis involving E2A

The model shows precursor progeny relationships in the lymphopoietic system denoted purple arrows. Transcriptional regulation is depicted using green arrows for positive regulation and red bars for negative regulation.