PD-1 is conserved from sharks to humans: new insights into PD-1, PD-L1, PD-L2, and SHP-2 evolution
Programmed cell death protein 1 (PD-1) is an immune checkpoint molecule until recently believed to exist only in tetrapod species. However, together with a very recent study dedicated to the CD28/CTLA4 molecule family, this study—using database information—identifies the PD-1 gene in both bony and c...
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| Format: | Article |
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1573492/full |
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| author | Ryohei Kondo Kohei Kondo Kei Nabeshima Akihiko Nishikimi Yasumasa Ishida Toshiaki Shigeoka Johannes M. Dijkstra |
| author_facet | Ryohei Kondo Kohei Kondo Kei Nabeshima Akihiko Nishikimi Yasumasa Ishida Toshiaki Shigeoka Johannes M. Dijkstra |
| author_sort | Ryohei Kondo |
| collection | DOAJ |
| description | Programmed cell death protein 1 (PD-1) is an immune checkpoint molecule until recently believed to exist only in tetrapod species. However, together with a very recent study dedicated to the CD28/CTLA4 molecule family, this study—using database information—identifies the PD-1 gene in both bony and cartilaginous fish, while being the first to present a detailed molecular analysis of the evolution of PD-1 and its ligands. Conserved sequence motifs imply an ancient origin of PD-1’s binding modes to its extracellular ligand PD-L1 and its intracellular ligand Src homology region 2 domain-containing phosphatase-2 (SHP-2), and also of its N116 glycosylation motif—a less well known PD-1 feature—important for binding galectins. The PD-1 cytoplasmic tail binds SHP-2 by two motifs, defined as an immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM), but sequence conservation patterns show that these definitions warrant a discussion. As in mammals, PD-1 transcripts in fish could be found co-expressed with markers of regulatory and exhausted T cells, suggesting a similar immune checkpoint function. Agreeing with previous reports, the PD-L1/PD-L2 gene duplication was only found in tetrapod species, while we newly discovered that features that consistently distinguish the two molecules are PD-L2 IgC domain motifs. Among PD-L1 (the name given to the single PD-L ancestral molecule) of many ray-finned fish, conservation of a very long cytoplasmic tail motif supports previous claims that PD-L1 cytoplasmic tails may have a function. Surprisingly, we found a gene similar to SHP-2—that we named SHP-2-like (SHP-2L)—to be conserved from sharks to mammals, although lost or inactivated in higher primates and rodents. SHP-2L is expected to bind PD-1 similar to SHP-2. This comparative analysis of PD-1 and its interacting molecules across jawed vertebrates highlights conserved immune checkpoint features while revealing new insights and lineage-specific adaptations. |
| format | Article |
| id | doaj-art-5a63b1b30be742929e4154c1c3aa35a0 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-5a63b1b30be742929e4154c1c3aa35a02025-08-20T03:48:14ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-05-011610.3389/fimmu.2025.15734921573492PD-1 is conserved from sharks to humans: new insights into PD-1, PD-L1, PD-L2, and SHP-2 evolutionRyohei Kondo0Kohei Kondo1Kei Nabeshima2Akihiko Nishikimi3Yasumasa Ishida4Toshiaki Shigeoka5Johannes M. Dijkstra6Biosafety Division, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, JapanAntimicrobial Resistance Research Center, National Institute of Infectious Diseases, Higashimurayama, Tokyo, JapanBiodiveristy Division, National Institute for Environmental Studies, Tsukuba, JapanBiosafety Division, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, JapanDivision of Biological Science, Nara Institute of Science and Technology, Nara, JapanDivision of Biological Science, Nara Institute of Science and Technology, Nara, JapanCenter for Medical Science, Fujita Health University, Toyoake, Aichi, JapanProgrammed cell death protein 1 (PD-1) is an immune checkpoint molecule until recently believed to exist only in tetrapod species. However, together with a very recent study dedicated to the CD28/CTLA4 molecule family, this study—using database information—identifies the PD-1 gene in both bony and cartilaginous fish, while being the first to present a detailed molecular analysis of the evolution of PD-1 and its ligands. Conserved sequence motifs imply an ancient origin of PD-1’s binding modes to its extracellular ligand PD-L1 and its intracellular ligand Src homology region 2 domain-containing phosphatase-2 (SHP-2), and also of its N116 glycosylation motif—a less well known PD-1 feature—important for binding galectins. The PD-1 cytoplasmic tail binds SHP-2 by two motifs, defined as an immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM), but sequence conservation patterns show that these definitions warrant a discussion. As in mammals, PD-1 transcripts in fish could be found co-expressed with markers of regulatory and exhausted T cells, suggesting a similar immune checkpoint function. Agreeing with previous reports, the PD-L1/PD-L2 gene duplication was only found in tetrapod species, while we newly discovered that features that consistently distinguish the two molecules are PD-L2 IgC domain motifs. Among PD-L1 (the name given to the single PD-L ancestral molecule) of many ray-finned fish, conservation of a very long cytoplasmic tail motif supports previous claims that PD-L1 cytoplasmic tails may have a function. Surprisingly, we found a gene similar to SHP-2—that we named SHP-2-like (SHP-2L)—to be conserved from sharks to mammals, although lost or inactivated in higher primates and rodents. SHP-2L is expected to bind PD-1 similar to SHP-2. This comparative analysis of PD-1 and its interacting molecules across jawed vertebrates highlights conserved immune checkpoint features while revealing new insights and lineage-specific adaptations.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1573492/fullPD-1PD-L1PD-L2SHP-1SHP-2SHP-2L |
| spellingShingle | Ryohei Kondo Kohei Kondo Kei Nabeshima Akihiko Nishikimi Yasumasa Ishida Toshiaki Shigeoka Johannes M. Dijkstra PD-1 is conserved from sharks to humans: new insights into PD-1, PD-L1, PD-L2, and SHP-2 evolution Frontiers in Immunology PD-1 PD-L1 PD-L2 SHP-1 SHP-2 SHP-2L |
| title | PD-1 is conserved from sharks to humans: new insights into PD-1, PD-L1, PD-L2, and SHP-2 evolution |
| title_full | PD-1 is conserved from sharks to humans: new insights into PD-1, PD-L1, PD-L2, and SHP-2 evolution |
| title_fullStr | PD-1 is conserved from sharks to humans: new insights into PD-1, PD-L1, PD-L2, and SHP-2 evolution |
| title_full_unstemmed | PD-1 is conserved from sharks to humans: new insights into PD-1, PD-L1, PD-L2, and SHP-2 evolution |
| title_short | PD-1 is conserved from sharks to humans: new insights into PD-1, PD-L1, PD-L2, and SHP-2 evolution |
| title_sort | pd 1 is conserved from sharks to humans new insights into pd 1 pd l1 pd l2 and shp 2 evolution |
| topic | PD-1 PD-L1 PD-L2 SHP-1 SHP-2 SHP-2L |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1573492/full |
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