Transcriptional regulation of lymphocyte development

Abstract

B lymphocytes and T lymphocytes develop from hematopoietic stem cells through a series of intermediates with progressively decreased lineage differentiation potential. Differentiation is preceded by increased accessibility of the chromatin at genes that are poised for expression in the progeny of a multipotent cell. During the process of differentiation there is increased expression of lineage-associated genes and repression of lineage-inappropriate genes resulting in commitment to differentiation through a specific lineage. These transcriptional events are coordinated by networks of transcription factors and their associated chromatin remodeling factors. The B lymphocyte lineage provides a paradigm for how these events unfold to promote specification and commitment to a single developmental pathway.

Figure 1

Precursor-progeny relationships in lymphopoiesis. HSCs with long-term (LT) and short-term (ST) self-renewal capacity generate cells of all hematopoietic lineages. Lymphoid specification is initiated as cells progress through the multipotent progenitor (MPP) and LMPP stage, concomitant with the up-regulation of Flt3 and loss of Mk/E differentiation potential. Mk/E progenitors (MEPs) may arise directly from the HSC pool. LMPPs are proposed migrate to the thymus where they differentiate into ETPs and generate specified DN2 and committed DN3 T-cells. In the BM, LMPPs further up-regulate lymphoid genes, namely Rag1 in ELPs and IL-7Rα in CLPs, and restrict G/M progenitor (GMP) potential. As B-cell differentiation progress, CLPs lose NK-cell potential. EBF1 activity, as evaluated by the expression of Igll1 (λ5), promotes B-lymphocyte commitment (BLCP) and differentiation to the pro-B cell stage. Surface markers that characterize, and allow for the isolation of, each population are indicated; L, Lineage (note that different lineage cocktails are used in the identification of different progenitors); S=Sca1; K=c-kit; 34=CD34; 25=CD25; MyP=myeloid progenitors; NK=NK lineage progenitors.

Figure 2

Transcriptional networks in B-cell specification and commitment. Transcriptional events are shown as cells progress from HSC to committed pro-B-lymphocytes. Alternative fates are depicted outside the grey box; transcription factors are represented with circle or oval borders while surface molecules are rod shaped. The connectors do not represent obligatory effector/target relationships.

Figure 3

Transcriptional networks in T-cell specification and commitment. Transcriptional events are shown as cells progress from LMPPs to committed DN3 thymocytes. Alternative fate are depicted outside the grey box; transcription factors are represented with circle or oval borders while surface molecules are rod shaped. The connectors do not represent obligatory effector/target relationships.