PD1-induced Shp2 condensation organizes inhibitory signalosomes through selective substrate partitioning

ABSTRACT The formation of microclusters is a hallmark of PD1 engagement with its ligands, yet the physical basis and functional significance of this phenomenon remain unclear. Here we show that ligand-bound PD1 licenses Shp2 self-association and liquid-liquid phase separation (LLPS), producing dynamic PD1:Shp2 condensates whose liquidity depends on Shp2 catalytic activity. Mutations that selectively disrupt Shp2 self-association weaken PD1 microcluster formation and impair PD1 inhibitory function. Mechanistically, PD1-induced Shp2 LLPS promotes the co-compartmentalization of signaling substrates such as CD3ζ and CD28, thereby facilitating its dephosphorylation. These findings identify Shp2 LLPS as an intrinsic organizing principle of the PD1 inhibitory pathway that links enzymatic activation, substrate selectivity and mesoscale assembly to suppress T cell activation. Competing Interest Statement E.H. consults for Tentarix Biotherapeutics. The other authors declare that they have no competing interests.