斯坦福大学医学院K. Christopher Garcia课题组近日取得一项新成果。经过不懈努力，他们开发出细胞因子受体字母表的扩展将T细胞重新编程为不同的状态。该项研究成果发表在2025年8月13日出版的《自然》上。

在这里，研究组利用共同γ链（γc）受体作为T细胞上的共享信号中枢，并通过正交细胞因子受体平台2,3,4强化天然和非天然异二聚体JAK-STAT受体配对的表达，以扩展γc信号编码。该团队测试了γc细胞因子、干扰素、IL-10和同源二聚体受体家族的受体，这些受体通常不与γc配对或在T细胞上不自然表达。这些受体模拟了它们的天然对应物，但也诱导了上下文独特的转录程序。这导致肿瘤中不同的T细胞命运，包括由正交GSCFR（oGCSFR）驱动的具有吞噬能力的骨髓样T细胞，以及由正交IL-4R（o4R）驱动的2型细胞毒性T（TC2）和辅助性T （TH2）细胞分化。具有IL-22R （o22R）和oGCSFR正交的T细胞（两者都不是在T细胞上天然表达的）表现出干细胞样和抗衰竭的转录和染色质景观，增强了抗肿瘤特性。非天然受体配对及其产生的JAK-STAT信号开辟了一条途径，使T细胞状态多样化，而不是由天然细胞因子诱导的。

据悉，T细胞通过受体二聚体响应细胞因子，这些受体二聚体在进化过程中被选择来激活典型的JAK-STAT信号传导和基因表达程序。然而，JAK-STAT受体配对的潜在组合多样性可以通过探索未开发的替代非自然配对的生物学来扩展。

附：英文原文

Title: Expanding the cytokine receptor alphabet reprograms T cells into diverse states

Author: Zhao, Yang, Ogishi, Masato, Pal, Aastha, Su, Leon L., Tao, Pingdong, Jiang, Hua, Rodriguez, Grayson E., Chen, Xiaojing, Sun, Qinli, Rysavy, Lea Wenting, Limsuwannarot, Sam, Waghray, Deepa, Kalbasi, Anusha, Garcia, K. Christopher

Issue&Volume: 2025-08-13

Abstract: T cells respond to cytokines through receptor dimers that have been selected over the course of evolution to activate canonical JAK–STAT signalling and gene expression programs1. However, the potential combinatorial diversity of JAK–STAT receptor pairings can be expanded by exploring the untapped biology of alternative non-natural pairings. Here we exploited the common γ chain (γc) receptor as a shared signalling hub on T cells and enforced the expression of both natural and non-natural heterodimeric JAK–STAT receptor pairings using an orthogonal cytokine receptor platform2,3,4 to expand the γc signalling code. We tested receptors from γc cytokines as well as interferon, IL-10 and homodimeric receptor families that do not normally pair with γc or are not naturally expressed on T cells. These receptors simulated their natural counterparts but also induced contextually unique transcriptional programs. This led to distinct T cell fates in tumours, including myeloid-like T cells with phagocytic capacity driven by orthogonal GSCFR (oGCSFR), and type 2 cytotoxic T (TC2) and helper T (TH2) cell differentiation driven by orthogonal IL-4R (o4R). T cells with orthogonal IL-22R (o22R) and oGCSFR, neither of which are natively expressed on T cells, exhibited stem-like and exhaustion-resistant transcriptional and chromatin landscapes, enhancing anti-tumour properties. Non-native receptor pairings and their resultant JAK–STAT signals open a path to diversifying T cell states beyond those induced by natural cytokines.

DOI: 10.1038/s41586-025-09393-1

Source: https://www.nature.com/articles/s41586-025-09393-1