Lineage plasticity and commitment in T‐cell development

Abstract

The earliest stages of intrathymic T-cell development include not only the acquisition of T-cell characteristics but also programmed loss of potentials for B, natural killer, and dendritic cell development. Evidence from genetics and cell-transfer studies suggests an order and some components of the mechanisms involved in loss of these options, but some of the interpretations conflict. The conflicts can be resolved by a view that postulates overlapping windows of developmental opportunity and individual mechanisms regulating progression along each pathway. This view is consistent with molecular evidence for the expression patterns of positive regulators of non-T developmental pathways, SCL, PU.1 and Id2, in early thymocytes. To some extent, overexpression of such regulators redirects thymocyte development in vitro. Specific commitment functions may normally terminate this developmental plasticity. Both PU.1 overexpression and stimulation of ectopically expressed growth factor receptors can perturb T- and myeloid/dendritic-cell divergence, but only in permissive stages. A cell-line system that approximates DN3-stage thymocytes reveals that PU.1 can alter specification even in a homogeneous population. However, the response of the population to PU.1 is sharply discontinuous. These studies show a critical role for regulatory context in restricting plasticity, which is probably maintained by interacting transcription factor networks.

Identification of a Novel Subpopulation of Human Cord Blood CD34−CD133−CD7−CD45+Lineage− Cells Capable of Lymphoid/NK Cell Differentiation After In Vitro Exposure to IL-15

“…Interestingly enough, high percentages of cells differentiated with IL-15 stained positively with both the anti-CD25 and the anti-CD44 mAb. These features were reminiscent of the early stages of normal T cell thymic development (12). In line with the exquisite sensitivity to IL-15, CD34 Ϫ CD133 Ϫ CD7 Ϫ CD45 dim lin Ϫ cells expressed high levels of the IL-2/IL-15R␥ chain (Table III).…”

“…The molecular events occurring during lineage restriction involve activation or silencing of genes encoding cytokine receptors, signal transduction molecules, and transcription factors (12)(13)(14). In this respect, the isolation of progenitor populations from normal in vivo sources can greatly contribute to the understanding of the process of differentiation and lineage plasticity, by providing access to intermediates that can be characterized by functional assays and molecular approaches (15)(16)(17).…”

Transcriptional priming of intrathymic precursors for dendritic cell development

“…Spi-B (Spib -Mouse Genome Informatics), an Ets family member that is highly related to PU.1, is also expressed in DN2 and DN3 cells, but Spib -/-thymocyte populations appear normal (Su et al, 1997). Roles for PU.1 and Spi-B in the T/DC lineage choice in the thymus are suggested by studies in which the overexpression of either PU.1 or Spi-B during the early stages of T-cell development diverted T cells to the DC lineage (Lefebvre et al, 2005;Rothenberg and Dionne, 2002). Interestingly, however, PU.1 and Spi-B appear to have distinct roles in DC development.…”

A Histone Methyltransferase ESET Is Critical for T Cell Development

“…Moderate interaction of TCR either with class I or class II MHC-bearing self-Ag allows immature thymocyte to become CD8 or CD4 single-positive (SP) T cells, respectively. It is well appreciated that moderate and strictly regulated activation of ERK is essential for positive selection (24,25).…”