{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:15:57Z","timestamp":1790810157258,"version":"4.1.0"},"posted":{"date-parts":[[2024,5,14]]},"group-title":"Immunology","reference-count":72,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T00:00:00Z","timestamp":1715644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,11,12]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>T cells have emerged as sex-dependent orchestrators of pain chronification but the sexually dimorphic mechanisms by which T cells control pain sensitivity is not resolved. Here, we demonstrate an influence of regulatory T cells (Tregs) on pain processing that is distinct from their canonical functions of immune regulation and tissue repair. Specifically, meningeal Tregs (mTregs) express the endogenous opioid, enkephalin, and mTreg-derived enkephalin exerts an antinociceptive action through a presynaptic opioid receptor signaling mechanism that is dispensable for immunosuppression. We demonstrate that mTregs are both necessary and sufficient to suppress mechanical pain sensitivity in female, but not male, mice, with this modulation reliant on sex hormones. These results uncover a fundamental sex-specific, and immunologically- derived endogenous opioid circuit for nociceptive regulation with critical implications for pain biology.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:p>1. Gating of allodynia by meningeal Tregs is sex hormone-dependent<\/jats:p>\n                  <jats:p>3. Treg-derived enkephalin modulates mechanical pain sensitivity, not inflammation<\/jats:p>\n                  <jats:p>\n                    4. Delta opioid receptor on MrgprD\n                    <jats:sup>+<\/jats:sup>\n                    sensory neuron mediates pain processing by mTregs\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.05.11.593442","type":"posted-content","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T07:20:32Z","timestamp":1715671232000},"source":"Crossref","is-referenced-by-count":8,"title":["Regulatory T cell-derived enkephalin gates nociception"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0364-8975","authenticated-orcid":false,"given":"\u00c9lora","family":"Midavaine","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz C.","family":"Moraes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Benitez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sian R.","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao M.","family":"Braz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan P.","family":"Kochhar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter L.","family":"Eckalbar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana I.","family":"Domingos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E.","family":"Pintar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan I.","family":"Basbaum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakeen W.","family":"Kashem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024111506000740000_2024.05.11.593442v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3360"},{"key":"2024111506000740000_2024.05.11.593442v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2007.02.006"},{"key":"2024111506000740000_2024.05.11.593442v2.3","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-018-0853-3"},{"key":"2024111506000740000_2024.05.11.593442v2.4","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-017-0816-0"},{"key":"2024111506000740000_2024.05.11.593442v2.5","doi-asserted-by":"publisher","DOI":"10.1017\/s0317167100006028"},{"key":"2024111506000740000_2024.05.11.593442v2.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.7414330"},{"key":"2024111506000740000_2024.05.11.593442v2.7","doi-asserted-by":"publisher","DOI":"10.2147\/IJWH.S151845"},{"key":"2024111506000740000_2024.05.11.593442v2.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.10.054"},{"key":"2024111506000740000_2024.05.11.593442v2.9","doi-asserted-by":"publisher","DOI":"10.1093\/cei\/uxac123"},{"key":"2024111506000740000_2024.05.11.593442v2.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.05.031"},{"key":"2024111506000740000_2024.05.11.593442v2.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.021"},{"key":"2024111506000740000_2024.05.11.593442v2.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.002"},{"key":"2024111506000740000_2024.05.11.593442v2.13","doi-asserted-by":"publisher","DOI":"10.1038\/528S137a"},{"key":"2024111506000740000_2024.05.11.593442v2.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.04.109"},{"key":"2024111506000740000_2024.05.11.593442v2.15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI122182"},{"key":"2024111506000740000_2024.05.11.593442v2.16","doi-asserted-by":"publisher","DOI":"10.1038\/nature11462"},{"key":"2024111506000740000_2024.05.11.593442v2.17","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001879"},{"key":"2024111506000740000_2024.05.11.593442v2.18","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.69056"},{"key":"2024111506000740000_2024.05.11.593442v2.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0824-5"},{"key":"2024111506000740000_2024.05.11.593442v2.20","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4528"},{"key":"2024111506000740000_2024.05.11.593442v2.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.04.019"},{"key":"2024111506000740000_2024.05.11.593442v2.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.01.008"},{"key":"2024111506000740000_2024.05.11.593442v2.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.03.002"},{"key":"2024111506000740000_2024.05.11.593442v2.24","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4053"},{"key":"2024111506000740000_2024.05.11.593442v2.25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2006895117"},{"key":"2024111506000740000_2024.05.11.593442v2.26","doi-asserted-by":"publisher","DOI":"10.1172\/JCI153805"},{"key":"2024111506000740000_2024.05.11.593442v2.27","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.005"},{"key":"2024111506000740000_2024.05.11.593442v2.28","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14967"},{"key":"2024111506000740000_2024.05.11.593442v2.29","doi-asserted-by":"publisher","DOI":"10.1177\/1744806919838191"},{"key":"2024111506000740000_2024.05.11.593442v2.30","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0008-17.2017"},{"key":"2024111506000740000_2024.05.11.593442v2.31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.648408"},{"key":"2024111506000740000_2024.05.11.593442v2.32","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.126751"},{"key":"2024111506000740000_2024.05.11.593442v2.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2024624118"},{"key":"2024111506000740000_2024.05.11.593442v2.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2023.103084"},{"key":"2024111506000740000_2024.05.11.593442v2.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2020.09.021"},{"key":"2024111506000740000_2024.05.11.593442v2.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.yfrne.2008.11.001"},{"key":"2024111506000740000_2024.05.11.593442v2.37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2000372117"},{"key":"2024111506000740000_2024.05.11.593442v2.38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2111315118"},{"key":"2024111506000740000_2024.05.11.593442v2.39","doi-asserted-by":"publisher","DOI":"10.1101\/2022.09.19.508325"},{"key":"2024111506000740000_2024.05.11.593442v2.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.10.010"},{"key":"2024111506000740000_2024.05.11.593442v2.41","doi-asserted-by":"publisher","DOI":"10.1038\/nature02033"},{"key":"2024111506000740000_2024.05.11.593442v2.42","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20222052"},{"key":"2024111506000740000_2024.05.11.593442v2.43","doi-asserted-by":"publisher","DOI":"10.1038\/307643a0"},{"key":"2024111506000740000_2024.05.11.593442v2.44","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf7844"},{"key":"2024111506000740000_2024.05.11.593442v2.45","doi-asserted-by":"publisher","DOI":"10.3791\/4105"},{"key":"2024111506000740000_2024.05.11.593442v2.46","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-023-02719-8"},{"key":"2024111506000740000_2024.05.11.593442v2.47","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001921"},{"key":"2024111506000740000_2024.05.11.593442v2.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.02.006"},{"key":"2024111506000740000_2024.05.11.593442v2.49","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2053-17.2017"},{"key":"2024111506000740000_2024.05.11.593442v2.50","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(84)90190-2"},{"key":"2024111506000740000_2024.05.11.593442v2.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2011.09.007"},{"key":"2024111506000740000_2024.05.11.593442v2.52","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000002934"},{"key":"2024111506000740000_2024.05.11.593442v2.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2021.01.023"},{"key":"2024111506000740000_2024.05.11.593442v2.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2012.05.003"},{"key":"2024111506000740000_2024.05.11.593442v2.55","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.91359.1"},{"key":"2024111506000740000_2024.05.11.593442v2.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.01.044"},{"key":"2024111506000740000_2024.05.11.593442v2.57","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(88)90122-4"},{"key":"2024111506000740000_2024.05.11.593442v2.58","doi-asserted-by":"publisher","DOI":"10.1016\/s0304-3959(99)00109-8"},{"key":"2024111506000740000_2024.05.11.593442v2.59","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17102-w"},{"key":"2024111506000740000_2024.05.11.593442v2.60","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-24-10906.2002"},{"key":"2024111506000740000_2024.05.11.593442v2.61","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14967"},{"key":"2024111506000740000_2024.05.11.593442v2.62","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2935"},{"key":"2024111506000740000_2024.05.11.593442v2.63","doi-asserted-by":"publisher","DOI":"10.2307\/2283398"},{"key":"2024111506000740000_2024.05.11.593442v2.64","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(94)90144-9"},{"key":"2024111506000740000_2024.05.11.593442v2.65","doi-asserted-by":"publisher","DOI":"10.1067\/S1526-5900(03)00781-8"},{"key":"2024111506000740000_2024.05.11.593442v2.66","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4281"},{"key":"2024111506000740000_2024.05.11.593442v2.67","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1801613"},{"key":"2024111506000740000_2024.05.11.593442v2.68","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22451"},{"key":"2024111506000740000_2024.05.11.593442v2.69","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61737-979-6_2"},{"key":"2024111506000740000_2024.05.11.593442v2.70","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.006668"},{"key":"2024111506000740000_2024.05.11.593442v2.71","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2000054"},{"key":"2024111506000740000_2024.05.11.593442v2.72","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1900-1"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.05.11.593442","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:26:14Z","timestamp":1768458374000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.05.11.593442"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,14]]},"references-count":72,"URL":"https:\/\/doi.org\/10.1101\/2024.05.11.593442","relation":{},"subject":[],"published":{"date-parts":[[2024,5,14]]},"subtype":"preprint"}}