Transcription factor YY1 is essential for iNKT cell development

Invariant natural killer T (iNKT) cells develop from CD4(+)CD8(+) double-positive (DP) thymocytes and express an invariant V(alpha)14-J(alpha)18 T-cell receptor (TCR) alpha-chain. Generation of these cells requires the prolonged survival of DP thymocytes to allow for V(alpha)14-J(alpha)18 gene rearrangements and strong TCR signaling to induce the expression of the iNKT lineage-specific transcription factor PLZF. Here, we report that the transcription factor Yin Yang 1 (YY1) is essential for iNKT cell formation. Thymocytes lacking YY1 displayed a block in iNKT cell development at the earliest progenitor stage. YY1-deficient thymocytes underwent normal V(alpha)14-J(alpha)18 gene rearrangements, but exhibited impaired cell survival. Deletion of the apoptotic protein BIM failed to rescue the defect in iNKT cell generation. Chromatin immunoprecipitation and deep-sequencing experiments demonstrated that YY1 directly binds and activates the promoter of the Plzf gene. Thus, YY1 plays essential roles in iNKT cell development by coordinately regulating cell survival and PLZF expression.