Expanding the cytokine receptor alphabet reprograms T cells into diverse states
- Yang Zhao
- Masato Ogishi
- Aastha Pal
- Leon L. Su
- Pingdong Tao
- Hua Jiang
- Grayson E. Rodriguez
- Xiaojing Chen
- Qinli Sun
- Lea Wenting Rysavy
- Sam Limsuwannarot
- Deepa Waghray
- Anusha Kalbasi
- K. Christopher Garcia
2025-08-13
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 programs 1 . 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 (γ 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 platform 2–4 to expand the γ c signalling code. We tested receptors from γ c cytokines as well as interferon, IL-10 and homodimeric receptor families that do not normally pair with γ 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 (T C 2) and helper T (T H 2) 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.