T cells normally respond to cytokines through receptor pairs that activate standard JAK–STAT signaling pathways. A recent study expanded the diversity of these signals by engineering T cells to express both natural and non-natural receptor pairings involving the common γ chain (γc), using an orthogonal cytokine receptor system. By introducing receptors not usually found on T cells, like those from interferon, IL-10, and homodimeric families, they generated unique transcriptional programs and distinct T cell fates in tumors. These included myeloid-like T cells with phagocytic ability, type 2 cytotoxic and helper T cells, and stem-like, exhaustion-resistant T cells with enhanced anti-tumor activity. Overall, non-native receptor pairings broaden the possible T cell states beyond what natural cytokines induce.
More reading:
Zhao, Y., Ogishi, M., Pal, A. et al. Expanding the cytokine receptor alphabet reprograms T cells into diverse states. Nature (2025). https://doi.org/10.1038/s41586-025-09393-1
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