Duke University, Department of Immunology, Durham, NC, 27710, USA.
Fox Chase Cancer Center, Blood Cell Development and Function Program, Philadelphia, PA, 19111, USA.
Nat Commun. 2022 Oct 6;13(1):5901. doi: 10.1038/s41467-022-33610-4.
Production of a functional peripheral T cell compartment typically involves massive expansion of the bone marrow progenitors that seed the thymus. There are two main phases of expansion during T cell development, following T lineage commitment of double-negative (DN) 2 cells and after successful rearrangement and selection for functional TCRβ chains in DN3 thymocytes, which promotes the transition of DN4 cells to the DP stage. The signals driving the expansion of DN2 thymocytes are well studied. However, factors regulating the proliferation and survival of DN4 cells remain poorly understood. Here, we uncover an unexpected link between the transcription factor Zfp335 and control of cGAS/STING-dependent cell death in post-β-selection DN4 thymocytes. Zfp335 controls survival by sustaining expression of Ankle2, which suppresses cGAS/STING-dependent cell death. Together, this study identifies Zfp335 as a key transcription factor regulating the survival of proliferating post-β-selection thymocytes and demonstrates a key role for the cGAS/STING pathway in driving apoptosis of developing T cells.
功能性外周 T 细胞区室的产生通常涉及到骨髓祖细胞的大量扩增，这些祖细胞为胸腺提供种子。在 T 细胞发育过程中有两个主要的扩增阶段，在双阴性（DN）2 细胞的 T 谱系承诺之后，以及在功能性 TCRβ 链在 DN3 胸腺细胞中的成功重排和选择之后，这促进了 DN4 细胞向 DP 阶段的过渡。驱动 DN2 胸腺细胞扩增的信号已得到很好的研究。然而，调节 DN4 细胞增殖和存活的因素仍知之甚少。在这里，我们揭示了转录因子 Zfp335 与 post-β-selection DN4 胸腺细胞中 cGAS/STING 依赖性细胞死亡控制之间的意外联系。Zfp335 通过维持 Ankle2 的表达来控制细胞存活，Ankle2 抑制 cGAS/STING 依赖性细胞死亡。总之，这项研究确定了 Zfp335 作为调节增殖后β选择胸腺细胞存活的关键转录因子，并证明了 cGAS/STING 途径在驱动发育中的 T 细胞凋亡中的关键作用。
