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

Cytokine receptor pairing rules, set by evolution, confine JAK-STAT signaling to a narrow region of a far larger combinatorial space. Of more than 1,200 pairings theoretically possible among the [~]36 JAK-associated human cytokine receptors, only [~]30-40 exist in nature. Using a double-orthogonal platform, we enforced pairings across the full all-by-all receptor matrix and resolved a fine-grained STAT atlas richer than the natural repertoire. Selected non-natural pairings generated emergent T cell states unpredictable from either parental receptor, with pairing orientation encoding signaling specificity. A synthetic IL-21R>IL-2R{beta} pairing, but not its reciprocal, drove a cytotoxic Tc17-like state, whereas natural IL-9R/{gamma}c drove a Tc1 fate despite similar STAT activation, showing that rebalancing quantitative STAT combinatorics can modulate T cell fate. Recombining IL-31R, not expressed in T cells, with STAT-biased receptor partners generated diverse states, several with superior antitumor efficacy. These findings define a non-natural pairing code for engineering synthetic T cell fates.