麻豆淫院

In 1992, graduate student Yasumasa Ishida discovered PD-1, marking the beginning of a journey that would make this molecule a major target in cancer immunotherapy. Now, Dr. Ishida and colleagues provide a comprehensive overview of the evolution of PD-1 and its interacting molecules. in Frontiers in Immunology, this new work underscores the essential nature of the PD-1 system across jawed vertebrates and offers interesting new molecular insights that may guide future immunotherapies.

PD-1 (programmed cell death 1; CD279) is a key immune checkpoint molecule and an effective target in cancer immunotherapy. This was discovered by Professor Tasuku Honjo at Kyoto University, and these findings earned him a share of the 2018 Nobel Prize in 麻豆淫院iology or Medicine, alongside Professor James Allison, for their "discovery of cancer therapy by inhibition of negative immune regulation."

The PD-1 research in Professor Honjo's lab began in the early 1990s, when Dr. Ishida, then a graduate student, identified the PD-1 gene. Dr. Ishida鈥攃urrently a group leader at the Nara Institute of Science and Technology鈥攈as always continued to study PD-1, and now, together with other Japanese researchers, reports a detailed analysis of the distribution and sequences of PD-1 and its ligands throughout jawed vertebrate species.

Since its in 1992, PD-1 was long believed to be exclusive to tetrapods (animals with four limbs). However, the consortium of Japanese researchers presents evidence that PD-1, along with its ligands PD-L1 and the phosphatases SHP-1 and SHP-2, and their critical interaction motifs, are conserved throughout jawed vertebrates, from sharks to humans.

These findings were made possible through the growing number of available whole-genome sequences. Notably, the presence of PD-1 in fish was independently by others very recently.

Key findings of the new Japanese study, with Dr. Ryohei Kondo鈥攁 former student of Dr. Ishida鈥攁s first author, include:

1. Residues forming hydrogen bonds between PD-1 and PD-L1 are well conserved throughout PD-1 and PD-L (including PD-L2) evolutionary history.
2. PD-L2, which emerged only in tetrapods, is consistently different from PD-L1 by unique motifs in its IgC domain.
3. (The ITIM and ITSM motif regions in the PD-1 cytoplasmic tail show conservation patterns that suggest a need for their redefinition.
4. Also in fish, PD-1 gene expression is predominantly associated with T cells, especially those with regulatory properties. This suggests a conserved role for PD-1 as an immune checkpoint.
5. A previously unrecognized ancient molecule, SHP-2-like (SHP-2L), is conserved across most jawed vertebrates but lost independently in rodents and higher primates.

Immune systems balance activation and inhibition, with activating pathways often discovered first. The PD-1 system was one of the last major components of the immune system without a known fish counterpart. Its discovery in sharks and bony fishes indicates that immune restraint via PD-1 is a deeply conserved feature across jawed vertebrates.

Dr. Kondo, of the National Center for Geriatrics and Gerontology, notes, "It's incredible to realize that immune checkpoint molecules like PD-1 are conserved across jawed vertebrates. It highlights the necessity of immune downregulation ability."

Dr. Ishida reflects, "It's deeply moving to see how a molecule I helped discover connects across 450 million years of evolution. In many ways, the circle has now come full."

Dr. Johannes (Hans) M. Dijkstra, a molecular evolution expert at Fujita Health University, adds, "Conservation reveals what is important, and the novel findings of conserved motifs in PD-1's ITIM and ITSM regions, as well as in PD-L2's IgC domain, may ultimately lead to novel therapeutic approaches targeting the PD-1 system."