{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T08:18:06Z","timestamp":1780733886415,"version":"3.54.1"},"reference-count":91,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The programmed cell death protein 1 (PDCD1 or PD-1) is a key regulatory immune checkpoint and a major target for therapeutic intervention. In oncology, antibodies blocking the PD-1 pathway are used to activate immune cells to promote anti tumour immunity while in immune-mediated inflammatory diseases, PD-1 agonist molecules have the potential to achieve immune suppression. NK cells are a specialised population of innate lymphocytes able to recognize a large range of distressed cells including damaged tissues in autoimmune and inflammatory conditions. Of note, NK cells can upregulate PD-1 expression upon activation and their effector functions can be modulated by the PD-1 signalling  pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We have generated a novel bispecific inhibitory molecule, comprised of a targeting domain highly specific for a pre-pro-insulin peptide presented by the HLA-A*02 molecules on the cell surface of pancreatic \u03b2-cells and a PD-1 agonist effector domain. Suppressive effects of the \u03b2-cell tethered bispecific PD-1 agonist molecule on NK cells  and NK92-PD-1 cell line activation were assessed through gene expression, cell surface expression of the CD107a degranulation marker, intracellular IFN\u03b3 production and Granzyme B secretion. EndoC-b cells proliferation and insulin production were also measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed that the bispecific PD-1 agonist molecules tethered to pancreatic b-cells accumulate at the immunological synapse, modify NK cell gene expression and decrease their inflammatory and cytotoxic functions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Targeted PD-1 agonist molecules, inhibiting T cells and NK cells in a tissue-specific manner offer a new promising treatment for autoimmune and inflammatory diseases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1640509","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T13:13:58Z","timestamp":1755868438000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Cell-targeted PD-1 agonists are potent NK-cell 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