Abstract
T-lineage committed precursor thymocytes are screened by a fate-determination process mediated via T cell receptor (TCR) signals for differentiation into distinct lineages. However, it remains unclear whether any antecedent event is required to couple TCR signals with the transcriptional program governing lineage decisions. Here we show that Bcl11b, known as a T-lineage commitment factor, is essential for proper expression of ThPOK and Runx3, central regulators for the CD4-helper/CD8-cytotoxic lineage choice. Loss of Bcl11b results in random expression of these factors and, thereby, lineage scrambling that is disconnected from TCR restriction by MHC. Initial Thpok repression by Bcl11b prior to the pre-selection stage is independent of a known silencer for Thpok, and requires the last zinc-finger motif in Bcl11b protein, which by contrast is dispensable for T-lineage commitment. Collectively, our findings shed new light on the function of Bcl11b in priming lineage-specifying genes to integrate TCR signals into subsequent transcriptional regulatory mechanisms.
Highlights
T-lineage committed precursor thymocytes are screened by a fate-determination process mediated via T cell receptor (TCR) signals for differentiation into distinct lineages
Our chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq) assay of total thymocytes detected that Bcl11b associated with Sth and proximal enhancer (PE) as well as intronic regions downstream from distal P1-promoter in the Thpok locus (Fig. 1d)
The hypomorphic Bcl11b mutation fails to control the expression of transcription factors, including T-helper-inducing POZ/Krueppel− like factor (ThPOK), Runx[3], and Foxp[3], which are important for specification of mature T lineages (CD4-helper, CD8-cytotoxic, and Treg, respectively)
Summary
T-lineage committed precursor thymocytes are screened by a fate-determination process mediated via T cell receptor (TCR) signals for differentiation into distinct lineages. Previous genetic studies for ‘gain and loss’ of ThPOK function demonstrated that its presence or absence in post-selection thymocytes is a major determinant of the CD4-helper (ThPOK+) versus CD8-cytotoxic (ThPOK–) lineage dichotomy[16,17,18] Consistent with these findings, expression of the Thpok gene is restricted to MHC-II selected thymocytes[16] in positively selected thymocytes. Thpok regulation has been recognized as an ideal model to study how TCR signals are coupled with the transcriptional program that establishes the identity of CD4+ helper T cells Such studies identified a transcriptional silencer in Thpok, hereafter denoted as Thpok silencer (Sth), which is an essential cis-acting element restricting Thpok expression to post-selection thymocytes in the helper lineage[19, 20]. Signals emanating from the IL-7 cytokine receptor have been shown to activate Runx[328, 29]; the intermediaries and their cisregulatory targets in Runx[3] remain to be established[30]
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