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Published 2016 | Accepted Version
Journal Article Open

Forging T-Lymphocyte Identity: Intersecting Networks of Transcriptional Control

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.

Additional Information

© 2016 Elsevier Inc. Available online 26 October 2015. The authors thank members of the Rothenberg group for discussion of the ideas presented here and for sharing relevant results before publication. Research in the Rothenberg lab was supported by grants from the USPHS, AI083514, AI095943, HD076915, and HL119102. J.U. was supported by the Swedish Research Council (Linköping University) and E.V.R. was supported by the Albert Billings Ruddock Professorship of Biology.

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August 22, 2023
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