Forging T-Lymphocyte Identity

Abstract

T lymphocyte development branches off from other lymphoid developmental programs through its requirement for sustained environmental signals through the Notch pathway. In the thymus, Notch signaling induces a succession of T-lineage regulatory factors that collectively create the T-cell identity through distinct steps. This process involves both the staged activation of T-cell identity genes and the staged repression of progenitor-cell-inherited regulatory genes once their roles in self-renewal and population expansion are no longer needed. With the recent characterization of Innate Lymphoid Cells (ILCs) that share transcriptional regulation programs extensively with T cell subsets, T-cell identity can increasingly be seen as defined in modular terms, as the processes selecting and actuating effector function are potentially detachable from the processes generating and selecting clonally unique T-cell receptor structures. The developmental pathways of different classes of T cells and ILCs are distinguished by the numbers of prerequisites of gene rearrangement, selection, and antigen contact before the cells gain access to nearly-common regulatory mechanisms for choosing effector function. Here, the major classes of transcription factors that interact with Notch signals during T-lineage specification are discussed in terms of their roles in these programs, the evidence for their spectra of target genes at different stages, and their cross-regulatory and cooperative actions with each other. Specific topics include Notch modulation of PU.1 and GATA-3, PU.1-Notch competition, the relationship between PU.1 and GATA-3, and the roles of E proteins, Bcl11b, and GATA-3 in guiding acquisition of T-cell identity while avoiding redirection to an ILC fate.

Immature CD8 Single-Positive Thymocytes Are a Molecularly Distinct Subpopulation, Selectively Dependent on BRD4 for Their Differentiation

“…Maturation from DN cells to ISP cells requires both the rearrangement of the TCRβ genes and extensive proliferation ( Rothenberg et al, 2016 ; Takahama et al, 1992 ). A defect in either TCRβ rearrangement or proliferation might result in a failure of BRD4-deleted DN cells to differentiate.…”

“…The generation of T cells in the thymus results from the sequential differentiation of a series of thymocyte precursors ( Mingueneau et al, 2013 ; Rothenberg et al, 2016 ; Vacchio et al, 2016 ). The earliest thymic immigrants from the bone marrow do not express any of the markers associated with mature T cells, namely the T cell receptor (TCR) and CD4/CD8 coreceptor molecules, and are called double negatives (DNs).…”

Programming for T-lymphocyte fates: modularity and mechanisms

“…Classic Notch-activated target genes such as Hes1, encoding a basic helixloop-helix repressor, are expressed throughout the specification process, although they are not T-lineage-specific. Interestingly, other Notch-dependent targets are also activated in different patterns from ETP to DN3a stage, showing that Notch signaling participates in a variety of stagedependent regulatory ensembles (for review, see Rothenberg et al 2016b). Only after β selection does the Notch input stop.…”

Fitting structure to function in gene regulatory networks

“…As multipotent blood cell precursors begin to differentiate toward a T-lymphocyte fate, they use a constellation of transcription factors that are partially held over from more pluripotent precursors and partially induced de novo by signals presented in the microenvironment of the body’s T cell “nursery”, the thymus (Rothenberg et al 2016; Yui and Rothenberg 2014). Among the transcription factors that are crucial for enabling cells to become T cells are a relatively T-cell specific factor, GATA-3, a factor used to make T and B lymphocytes, E2A, and a factor used for various non-T cell fates as well as the early steps of T-cell development, PU.1.…”