Analysis of Bcl11b function during thymocyte Differentiation

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It has been shown that any post-selection DP thymocytes differentiate into CD4-lineage upon expression of ThPOK, whereas they become CD8-linage cells in the absence of ThPOK. Therefore it is crucial to understand how helper-lineage specific expression of ThPOK gene is regulated. We have identified a ThPOK silencer in the ThPOK gene that is essential to repress ThPOK gene during differentiation of MHC class I selected cells toward the cytotoxic-lineage.In order to reveal regulation of ThPOK silencer activity, we performed pull down affinity purification with the functional shorter silencer sequences. After molecular and biological screening of several candidates obtained by the above approach, Bcl11b transcription factor appeared to play an essential role in activating ThPOK silencer. Genetic analysis of Bcl11b conditional knock-out mice showed that de-repression of ThPOK in both pre-selection thymocyte and in MHC class I selected cells, resulting in cell fate conversion of MHC class I selected cells to CD4^+helper lineage cells. These results suggested that Bcl11b is central to regulate helper/cytotoxic lineage decision by lymphocytes via regulation of ThPOK silencer activity.