Transmembrane domain-driven PD-1 dimers mediate T cell inhibition

Sci Immunol. 2024 Mar 8;9(93):eade6256. doi: 10.1126/sciimmunol.ade6256. Epub 2024 Mar 8.


Programmed cell death-1 (PD-1) is a potent immune checkpoint receptor on T lymphocytes. Upon engagement by its ligands, PD-L1 or PD-L2, PD-1 inhibits T cell activation and can promote immune tolerance. Antagonism of PD-1 signaling has proven effective in cancer immunotherapy, and conversely, agonists of the receptor may have a role in treating autoimmune disease. Some immune receptors function as dimers, but PD-1 has been considered monomeric. Here, we show that PD-1 and its ligands form dimers as a consequence of transmembrane domain interactions and that propensity for dimerization correlates with the ability of PD-1 to inhibit immune responses, antitumor immunity, cytotoxic T cell function, and autoimmune tissue destruction. These observations contribute to our understanding of the PD-1 axis and how it can potentially be manipulated for improved treatment of cancer and autoimmune diseases.

MeSH terms

  • Autoimmune Diseases*
  • Humans
  • Immune Tolerance
  • Lymphocyte Activation
  • Neoplasms*
  • Programmed Cell Death 1 Receptor
  • Protein Domains


  • Programmed Cell Death 1 Receptor