biostudies-literatureUnknown645(8082)Zhao YT 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 (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 wNature1039-1050https://www.ebi.ac.uk/biostudies/studies/S-EPMC12460165biostudies-literatureExpanding the cytokine receptor alphabet reprograms T cells into diverse states.PMC12460165Ogishi MWaghray DGarcia KCJiang HPal AKalbasi AZhao YRysavy LWSun QRodriguez GESu LLChen XLimsuwannarot STao PfalseExpanding the cytokine receptor alphabet reprograms T cells into diverse states.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 (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 w2025-01-01T00:00:00Z2025 Sep2026-06-03T19:37:50.943Z2026-04-30T03:12:27.299ZS-EPMC124601654080451910.1038/s41586-025-09393-1