{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T20:42:37Z","timestamp":1793824957620,"version":"4.6.1"},"reference-count":96,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T00:00:00Z","timestamp":1703116800000},"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:p>CD4 and LAG-3 are related molecules that are receptors for MHC class II molecules. Their major functional differences are situated in their cytoplasmic tails, in which CD4 has an activation motif and LAG-3 an inhibitory motif. Here, we identify shark <jats:italic>LAG-3<\/jats:italic> and show that a previously identified shark <jats:italic>CD4-like<\/jats:italic> gene has a genomic location, expression pattern, and motifs similar to <jats:italic>CD4<\/jats:italic> in other vertebrates. In nurse shark (<jats:italic>Ginglymostoma cirratum<\/jats:italic>) and cloudy catshark (<jats:italic>Scyliorhinus torazame<\/jats:italic>), the highest <jats:italic>CD4<\/jats:italic> expression was consistently found in the thymus whereas such was not the case for <jats:italic>LAG-3<\/jats:italic>. Throughout jawed vertebrates, the CD4 cytoplasmic tail possesses a Cx(C\/H) motif for binding kinase LCK, and the LAG-3 cytoplasmic tail possesses (F\/Y)xxL(D\/E) including the previously determined FxxL inhibitory motif resembling an immunoreceptor tyrosine-based inhibition motif (ITIM). On the other hand, the acidic end of the mammalian LAG-3 cytoplasmic tail, which is believed to have an inhibitory function as well, was acquired later in evolution. The present study also identified <jats:italic>CD4-1<\/jats:italic>, <jats:italic>CD4-2<\/jats:italic>, and <jats:italic>LAG-3<\/jats:italic> in the primitive ray-finned fishes bichirs, sturgeons, and gars, and experimentally determined these sequences for sterlet sturgeon (<jats:italic>Acipenser ruthenus<\/jats:italic>). Therefore, with CD4-1 and CD4-2 already known in teleosts (modern ray-finned fish), these two CD4 lineages have now been found within all major clades of ray-finned fish. Although different from each other, the cytoplasmic tails of ray-finned fish CD4-1 and chondrichthyan CD4 not only contain the Cx(C\/H) motif but also an additional highly conserved motif which we expect to confer a function. Thus, although restricted to some species and gene copies, in evolution both CD4 and LAG-3 molecules appear to have acquired functional motifs besides their canonical Cx(C\/H) and ITIM-like motifs, respectively. The presence of CD4 and LAG-3 molecules with seemingly opposing functions from the level of sharks, the oldest living vertebrates with a human-like adaptive immune system, underlines their importance for the jawed vertebrate immune system. It also emphasizes the general need of the immune system to always find a balance, leading to trade-offs, between activating and inhibiting processes.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1267743","type":"journal-article","created":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T04:47:38Z","timestamp":1703134058000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["CD4 and LAG-3 from sharks to humans: related molecules with motifs for opposing functions"],"prefix":"10.3389","volume":"14","author":[{"given":"Fumio","family":"Takizawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichiro","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuichiro","family":"Miyazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Ohta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Ver\u00edssimo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin F.","family":"Flajnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Parra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Tokunaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Suetake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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