转录因子Bcl11b在T细胞分化发育及其谱系维持中起着关键的作用。我们已经证明了T细胞中Bcl11b基因功能的缺失会诱导T细胞重编程为一种全新的，类似NK细胞的肿瘤杀伤细胞（ITNK）。进一步实验显示：ITNK细胞能高效地杀死多种组织来源的肿瘤细胞，从而在体内抑制肿瘤生长与转移。并且，ITNK细胞不需依赖MHC-I分子来识别肿瘤细胞，也不会攻击宿主正常细胞。然而，哪些转录因子参与T细胞重编程为ITNK细胞的过程和ITNK细胞识别肿瘤的机理尚不清楚。为了进一步理解此重编程的分子机制，本项目拟通过联合'功能获得'和'功能缺失'等实验手段来研究Bcl11b下游分子调控网络。同时，本项目还将通过研究ITNK细胞的表面识别受体和TCR功能来了解其对肿瘤细胞的识别和杀伤机制。该项目有望揭示体外高效诱导人体ITNK细胞产生的方法，并为将ITNK细胞应用于癌症免疫疗法提供更充分的科学依据。

Transcription factor Bcl11b is essential for T cell development and the maintenance of T cell identity. T cells reprogram to NK-like cells (ITNKs) upon loss of Bcl11b. ITNKs are capable of killing tumor cells regardless of MHC-I expression in targets in vitro and suppressing tumor metastasis in vivo. To dissect molecular mechanisms involved in the reprogramming process, we propose to combine 'gain of function' and 'loss of function' to study Bcl11b downstream networks. We will also use ChIP-seq technology to indentify genes that are directly regulated by Bcl11b. To further characterize ITNKs, we will validate whether ITNKs can use TCR receptors, in addition to NK recognition receptors, to recognize tumor targets. The knowledge obtained from this study will help us generate ITNKs from human T cells and access the feasibility of ITNKs application in cancer immunotherapy.