CCR6-targeted PD-1 agonism to expand intragraft Tregs without blunting systemic immunity

PD-1 signaling can sustain Treg proliferation during transplant tolerance (Leung et al., 2018), yet systemic PD-1 agonism risks broad immunosuppression. Single-cell studies of operationally tolerant kidney recipients report increased Tregs with high CCR6 expression (Bae et al., 2023). This idea designs bispecific nanobodies or ligand-fusion biologics that bind CCR6 and deliver a PD-1 agonistic cue, optionally packaged in nanoparticles optimized for graft homing. The agent should preferentially activate PD-1 on CCR6+ Tregs within the graft, amplifying local tolerance. This challenges the assumption that checkpoint modulation must be global (Li et al., 2020), and it complements antigen-specific Treg transfer (Seltrecht et al., 2024) by providing a survival/proliferation niche signal. Single-cell and spatial transcriptomics would verify Treg-specific PD-1 pathway engagement and rule out Teff suppression. If validated, this could be a blueprint for “checkpoint agonism with address labels” in transplantation and autoimmunity.

References:

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