美国国立卫生研究院Alfred Singer研究组的研究揭示了在逃避克隆缺失后，自体反应性胸腺细胞如何分化为调节性和效应性CD4⁺ T细胞。相关论文于2023年3月23日发表在《自然—免疫学》杂志上。

研究人员表明在胸腺选择的不同时间缺失和分化是激动剂信号，并且调节性T（T_reg）和效应T（T_eff）细胞都是在克隆缺失后产生的，并作为激动剂信号决定CD4⁺ CD25⁺前体细胞的谱系命运。破坏激动剂信号传导会诱导CD4⁺ CD25⁺前体表达Foxp3并发育为T_reg细胞，而持续激动剂信号传导诱导CD4⁺ CD25⁺前体分化为IL-2⁺ T_eff细胞。值得注意的是，研究发现转化生长因子β通过破坏较弱的激动剂信号诱导Foxp3表达并促进T_reg细胞发育，并且Foxp3表达不是由IL-2诱导的，除非在非生理体内条件下。因此，TCR信号破坏与持久性是胸腺中细胞谱系命运决定的普遍机制，其调控激动剂信号自身反应性胸腺细胞的发育。

研究人员表示携带自身反应性T细胞受体（TCR）的胸腺细胞由TCR/共刺激分子发出激动剂信号激活，进行克隆缺失或分化为专门的T_reg或T_eff CD4⁺细胞。对发育过程中如何实现细胞不同的命运决定仍知之甚少。

附：英文原文 

Title: How autoreactive thymocytes differentiate into regulatory versus effector CD4+ T cells after avoiding clonal deletion

Author: Tai, Xuguang, Indart, Alyssa, Rojano, Mirelle, Guo, Jie, Apenes, Nicolai, Kadakia, Tejas, Craveiro, Marco, Alag, Amala, Etzensperger, Ruth, Badr, Mohamed Elsherif, Zhang, Flora, Zhang, Zhongmei, Mu, Jie, Guinter, Terry, Crossman, Assiatu, Granger, Larry, Sharrow, Susan, Zhou, Xuyu, Singer, Alfred

Issue&Volume: 2023-03-23

Abstract: Thymocytes bearing autoreactive T cell receptors (TCRs) are agonist-signaled by TCR/co-stimulatory molecules to either undergo clonal deletion or to differentiate into specialized regulatory T (Treg) or effector T (Teff) CD4+ cells. How these different fates are achieved during development remains poorly understood. We now document that deletion and differentiation are agonist-signaled at different times during thymic selection and that Treg and Teff cells both arise after clonal deletion as alternative lineage fates of agonist-signaled CD4+CD25+ precursors. Disruption of agonist signaling induces CD4+CD25+ precursors to initiate Foxp3 expression and become Treg cells, whereas persistent agonist signaling induces CD4+CD25+ precursors to become IL-2+ Teff cells. Notably, we discovered that transforming growth factor-β induces Foxp3 expression and promotes Treg cell development by disrupting weaker agonist signals and that Foxp3 expression is not induced by IL-2 except under non-physiological in vivo conditions. Thus, TCR signaling disruption versus persistence is a general mechanism of lineage fate determination in the thymus that directs development of agonist-signaled autoreactive thymocytes.

DOI: 10.1038/s41590-023-01469-2

Source: https://www.nature.com/articles/s41590-023-01469-2