Expanding the cytokine receptor alphabet reprograms T cells into diverse states

• 成果类型: Article
• 署名作者: 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
• 署名单位: Stanford Medicine; Stanford University; Stanford Medicine; Stanford University; Stanford University; Stanford Medicine; Stanford Cancer Institute; Howard Hughes Medical Institute; Stanford Medicine; Stanford University; Stanford University; Stanford Medicine
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09393-1
• 发表日期: 2025-09-25
• 关键词: complex reveals; activation; cancer; differentiation; interleukin-22; progenitors; il-10

摘要

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 gamma chain (gamma c) 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 gamma c signalling code. We tested receptors from gamma c cytokines as well as interferon, IL-10 and homodimeric receptor families that do not normally pair with gamma c 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.