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- Title
Transmembrane domain–driven PD-1 dimers mediate T cell inhibition.
- Authors
Philips, Elliot A.; Liu, Jia; Kvalvaag, Audun; Mørch, Alexander M.; Tocheva, Anna S.; Ng, Charles; Liang, Hong; Ahearn, Ian M.; Pan, Ruimin; Luo, Christina C.; Leithner, Alexander; Qin, Zhihua; Zhou, Yong; Garcia-España, Antonio; Mor, Adam; Littman, Dan R.; Dustin, Michael L.; Wang, Jun; Kong, Xiang-Peng
- Abstract
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. Editor's Summary: Programmed cell death-1 (PD-1) is well known as an immune checkpoint receptor on T cells that can inhibit activation upon engagement with its ligands PD-L1 or PD-L2. PD-1 has largely been considered to function as a monomer, but Philips et al. now show that PD-1 can form dimers in cis via transmembrane domain interactions. They observed that limiting PD-1 dimerization weakens T cell inhibition upon ligand engagement, which enhances antitumor and cytotoxic T cell function and promotes autoimmunity. These findings may shape ongoing efforts to more effectively block PD-1 function or, conversely, to develop PD-1 agonists. —Christiana Fogg
- Subjects
KONINKLIJKE Philips NV; PROGRAMMED cell death 1 receptors; T cells; CYTOTOXIC T cells; T cell receptors; TRANSMEMBRANE domains; DIMERS
- Publication
Science Immunology, 2024, Vol 9, Issue 93, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.ade6256