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Interaction with the ligand ADPN inhibits T-cell responses, but given the existence of multiple AdipoR ligands, we hypothesize that ligand diversity underlies its differential effect in T-cell immunity. To test this, we use tilapia and mouse models. Tilapia encodes AdipoR1 but lacks ADPN. Instead, an alternative adipokine, CTRP9, engages AdipoR1. We find CTRP9\u2013AdipoR1 interaction triggers Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx and activates the CaM\u2013CaMKK\u03b2\u2013AMPK pathway, facilitating crosstalk with TCR signaling. This cascade enhances T-cell activation, proliferation, and antimicrobial immunity by promoting glycolysis. In mice, CTRP9 similarly enhances T-cell activation, proliferation, and cytokine production and improves the efficacy of anti-CD19 CAR-T cells in eliminating B-cell lymphoma in vitro. These findings reveal an evolutionarily conserved role of CTRP9 in promoting T-cell immunity, in contrast to the inhibitory effect exerted by ADPN. Mechanistically, CTRP9 and ADPN exert distinct effects on T-cell metabolism; CTRP9 enhances T-cell glycolysis, whereas ADPN suppresses it. We therefore propose ligand selectivity as a determinant of AdipoR1-dependent T-cell immune outcomes.\n                  <\/jats:p>","DOI":"10.1038\/s44319-025-00640-0","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T14:35:45Z","timestamp":1763390145000},"page":"6437-6459","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CTRP9 engages AdipoR1 and promotes T cell glycolysis and immunity"],"prefix":"10.1038","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5065-6399","authenticated-orcid":false,"given":"Kunming","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiansong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haokai","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhai","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhuo","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Geng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuying","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2253-8181","authenticated-orcid":false,"given":"Xiumei","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3112-5012","authenticated-orcid":false,"given":"Jialong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"640_CR1","doi-asserted-by":"crossref","first-page":"e1010913","DOI":"10.1371\/journal.ppat.1010913","volume":"18","author":"K Ai","year":"2022","unstructured":"Ai K, Li K, Jiao X, Zhang Y, Li J, Zhang Q, Wei X, Yang J (2022) IL-2-mTORC1 signaling coordinates the STAT1\/T-bet axis to ensure Th1 cell differentiation and anti-bacterial immune response in fish. 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