The extent to which JAK/STAT cytokine signaling is functionally redundant or selective remains debated. Here we engineered a double orthogonal IL-2/IL-2R{beta}/{gamma}c ternary system enabling programmable, interference-free activation of each of the 36 mammalian cytokine receptors, and their downstream six STATs, in T cells. At the membrane-proximal level, comprehensive phospho-signaling profiling revealed that while each receptor activates a dominant STAT, unique STAT activation fingerprints derived from combinatorial biases fine-tune nuanced T cell fates. At the membrane-distal level, single-cell transcriptomic atlas of all cytokine receptors confirmed that these STAT mosaics sensitively specify non-redundant transcriptional programs. STAT5-dominant receptors drove proliferative expansion at the expense of stemness; STAT3-driven programs instructed a continuum from stem cell memory to terminal effector states with preserved cytotoxic capacity and mediated superior curative antitumor responses; while other STATs specified highly restricted phenotypes. These findings decode a STAT signaling vocabulary that defines the intrinsic functional bandwidth of natural cytokines.
Tao, P., Rastogi, R., Jiang, H., Zhao, Y., Su, L. L., Jude, K., Kundaje, A., Garcia, K. C.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 26
- Comments 0