All-by-All Cytokine Receptor Pairing Network Unlocks Coding of Non-Natural T Cell States

The evolutionarily determined rules governing cytokine receptor pairing restrict Janus kinase-STAT signaling to a limited subset of a much larger possible combination space. Among the roughly 1,200 potential receptor pairings in the human genome, only around 30-40 occur naturally. Employing a double-orthogonal platform, researchers expanded the cytokine receptor matrix to encompass all possible pairings, enabling the identification of a highly detailed STAT activation landscape surpassing the natural repertoire.

Some of these engineered pairings yielded novel T cell states not observed in nature, with the orientation of the receptor pairing critical in determining the specificity of the signaling response. For instance, a synthetic pairing of IL-21 receptor with IL-2 receptor beta, but not its reverse, induced a cytotoxic Tc17-like phenotype.

In contrast, natural IL-9 receptor and gamma-c pairing promoted a Tc1 fate, despite comparable STAT activation levels, indicating that fine-tuning the quantitative balance of STAT signaling can dictate T cell lineage commitment. Moreover, incorporating the IL-31 receptor, which is not expressed in T cells, with STAT-biased receptor partners yielded a range of distinct T cell states, several of which demonstrated enhanced antitumor capabilities.

Collectively, these results establish a non-natural cytokine receptor pairing code that can be leveraged to design synthetic T cell fates with tailored functional properties.