{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:15:02Z","timestamp":1768522502483,"version":"3.49.0"},"posted":{"date-parts":[[2025,7,8]]},"group-title":"Immunology","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"SecretarM-CM--a de EducaciM-CM-3n, Ciencia, TecnologM-CM-a e InnovaciM-CM-3n de la Ciudad de MM-CM-)xico","award":["SECTEI\/130\/2023"],"award-info":[{"award-number":["SECTEI\/130\/2023"]}]},{"name":"NIH","award":["R35\/MIRA"],"award-info":[{"award-number":["R35\/MIRA"]}]},{"name":"Damon-Runyon Rachleff Innovation Award","award":["73-22"],"award-info":[{"award-number":["73-22"]}]},{"name":"JDRF Innovative award","award":["1-INO-2023-1342-A-N"],"award-info":[{"award-number":["1-INO-2023-1342-A-N"]}]},{"name":"Richard Ranti"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The one-carbon metabolic pathway is essential for proliferating cells and has recently been identified as an immunomodulatory target in CD4\u207a T cells. However, its role in other immune cell types has not been fully established. We investigated the function of the one-carbon pathway in CD8\u207a T cells, which are the primary effectors responsible for the destruction of pancreatic beta cells that causes type 1 diabetes. Enzymes involved in the one-carbon pathway, as well as levels of formate\u2014a critical intermediate\u2014were upregulated during CD8\u207a T-cell activation. Pharmacological inhibition of MTHFD2, a mitochondrial enzyme involved in one-carbon metabolism, suppressed CD8\u207a T-cell activation, proliferation, and effector function. Mechanistically, this effect was mediated by reduced signaling through KRAS and the mTORC1 downstream targets HIF1\u03b1, S6, and STAT3. As previously shown in CD4\u207a T cells, formate supplementation reversed the effects of MTHFD2 inhibition on activation, proliferation, and function of CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells, and prevented the reduction of the TCF1\n                  <jats:sup>high<\/jats:sup>\n                  CD8\u207a progenitor cell population, which has been shown to drive anti-beta cell autoimmunity. Formate levels were elevated in the immune cells isolated from pancreatic lymph nodes during the insulitis stage in non-obese diabetic mice. Treatment of euglycemic non-obese diabetic mice with an MTHFD2 inhibitor during the insulitis stage delayed CD8\u207a T-cell infiltration into pancreatic islets and postponed the onset of type 1 diabetes. These findings reveal a new paradigm for preventing and delaying the onset of type 1 diabetes.\n                <\/jats:p>","DOI":"10.1101\/2025.07.04.663229","type":"posted-content","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T08:10:24Z","timestamp":1752221424000},"source":"Crossref","is-referenced-by-count":1,"title":["Inhibition of formate production blocks CD8\n                  <sup>+<\/sup>\n                  T-cell responses and delays disease onset in a mouse model of type 1 diabetes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0996-9158","authenticated-orcid":false,"given":"Gabriela","family":"Ramirez-Hernandez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4472-6367","authenticated-orcid":false,"given":"Micah","family":"Bell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7916-7422","authenticated-orcid":false,"given":"Byungsoo","family":"Kong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3998-0122","authenticated-orcid":false,"given":"Samuel","family":"Block","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6702-4192","authenticated-orcid":false,"given":"Matthew G.","family":"Vander Heiden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5307-9021","authenticated-orcid":false,"given":"Nora","family":"Kory","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025071101101463000_2025.07.04.663229v1.1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.665133"},{"key":"2025071101101463000_2025.07.04.663229v1.2","doi-asserted-by":"crossref","unstructured":"Alice Long , S, Jerill Thorpe , Hannah A DeBerg , Vivian Gersuk , James A Eddy , Kristina M Harris , Mario Ehlers , Kevan C Herold , Gerald T Nepom , and Peter S Linsley . 2016. \u201cPartial Exhaustion of CD8 T Cells and Clinical Response to Teplizumab in New-Onset Type 1 Diabetes.\u201d https:\/\/www.science.org.","DOI":"10.1126\/sciimmunol.aai7793"},{"key":"2025071101101463000_2025.07.04.663229v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.09.016"},{"key":"2025071101101463000_2025.07.04.663229v1.4","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad0489"},{"key":"2025071101101463000_2025.07.04.663229v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2536"},{"key":"2025071101101463000_2025.07.04.663229v1.6","doi-asserted-by":"publisher","DOI":"10.1006\/clim.2000.4882"},{"key":"2025071101101463000_2025.07.04.663229v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0203-y"},{"key":"2025071101101463000_2025.07.04.663229v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-02401004-9"},{"key":"2025071101101463000_2025.07.04.663229v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-022-00965-1"},{"key":"2025071101101463000_2025.07.04.663229v1.10","doi-asserted-by":"publisher","DOI":"10.1900\/RDS.2012.9.169"},{"key":"2025071101101463000_2025.07.04.663229v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.04.016"},{"key":"2025071101101463000_2025.07.04.663229v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.08.009"},{"key":"2025071101101463000_2025.07.04.663229v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-96327-2"},{"key":"2025071101101463000_2025.07.04.663229v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.05.043"},{"key":"2025071101101463000_2025.07.04.663229v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcpro.2024.100801"},{"key":"2025071101101463000_2025.07.04.663229v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04248-x"},{"key":"2025071101101463000_2025.07.04.663229v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-023-00771-5"},{"key":"2025071101101463000_2025.07.04.663229v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2021.100961"},{"key":"2025071101101463000_2025.07.04.663229v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41374-018-0137-1"},{"key":"2025071101101463000_2025.07.04.663229v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-023-00985-4"},{"key":"2025071101101463000_2025.07.04.663229v1.21","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djy160"},{"key":"2025071101101463000_2025.07.04.663229v1.22","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01113"},{"key":"2025071101101463000_2025.07.04.663229v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2016.16"},{"key":"2025071101101463000_2025.07.04.663229v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109447"},{"key":"2025071101101463000_2025.07.04.663229v1.25","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat9528"},{"key":"2025071101101463000_2025.07.04.663229v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2020.12.001"},{"key":"2025071101101463000_2025.07.04.663229v1.27","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-014-1738-7"},{"key":"2025071101101463000_2025.07.04.663229v1.28","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2012-0552"},{"key":"2025071101101463000_2025.07.04.663229v1.29","doi-asserted-by":"publisher","DOI":"10.3390\/metabo12070652"},{"key":"2025071101101463000_2025.07.04.663229v1.30","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-025-03945-y"},{"key":"2025071101101463000_2025.07.04.663229v1.31","doi-asserted-by":"crossref","unstructured":"Lieberman, Scott M , Anne M Evans , Bingye Han , Toshiyuki Takaki , Yuliya Vinnitskaya , Jennifer A Caldwell , David V Serreze , et al. 2003. \u201cIdentification of the Cell Antigen Targeted by a Prevalent Population of Pathogenic CD8 T Cells in Autoimmune Diabetes.\u201d www.pnas.orgcgidoi10.1073pnas.0932778100.","DOI":"10.1073\/pnas.0932778100"},{"key":"2025071101101463000_2025.07.04.663229v1.32","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0000000000000488"},{"key":"2025071101101463000_2025.07.04.663229v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2025.104372"},{"key":"2025071101101463000_2025.07.04.663229v1.34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2000006"},{"key":"2025071101101463000_2025.07.04.663229v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.12.011"},{"key":"2025071101101463000_2025.07.04.663229v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2012.04.004"},{"key":"2025071101101463000_2025.07.04.663229v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101093"},{"key":"2025071101101463000_2025.07.04.663229v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4128"},{"key":"2025071101101463000_2025.07.04.663229v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2021.109083"},{"key":"2025071101101463000_2025.07.04.663229v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/s44324-024-00005-6"},{"key":"2025071101101463000_2025.07.04.663229v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2015.08.019"},{"key":"2025071101101463000_2025.07.04.663229v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2019.05.012"},{"key":"2025071101101463000_2025.07.04.663229v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2014.11.005"},{"key":"2025071101101463000_2025.07.04.663229v1.44","doi-asserted-by":"crossref","unstructured":"Rao, Enyu , Yuwen Zhang , Qiang Li , Jiaqing Hao , Nejat K Egilmez , Jill Suttles , and Bing Li . 2016. \u201cAMPK-Dependent and Independent Effects of AICAR and Compound C on T-Cell Responses.\u201d www.impactjournals.com\/oncotarget.","DOI":"10.18632\/oncotarget.9277"},{"key":"2025071101101463000_2025.07.04.663229v1.45","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1521"},{"key":"2025071101101463000_2025.07.04.663229v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.06.007"},{"key":"2025071101101463000_2025.07.04.663229v1.47","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-22-1301"},{"key":"2025071101101463000_2025.07.04.663229v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2014.10.006"},{"key":"2025071101101463000_2025.07.04.663229v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112481"},{"key":"2025071101101463000_2025.07.04.663229v1.50","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-005-1848-6"},{"key":"2025071101101463000_2025.07.04.663229v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.10.011"},{"key":"2025071101101463000_2025.07.04.663229v1.52","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1257107"},{"key":"2025071101101463000_2025.07.04.663229v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.01.021"},{"key":"2025071101101463000_2025.07.04.663229v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-00982-6"},{"key":"2025071101101463000_2025.07.04.663229v1.55","doi-asserted-by":"publisher","DOI":"10.3390\/cells10102603"},{"key":"2025071101101463000_2025.07.04.663229v1.56","doi-asserted-by":"publisher","DOI":"10.1172\/JCI126595"},{"key":"2025071101101463000_2025.07.04.663229v1.57","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2024.1377322"},{"key":"2025071101101463000_2025.07.04.663229v1.58","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-021-01189-2"},{"key":"2025071101101463000_2025.07.04.663229v1.59","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2018.6767"},{"key":"2025071101101463000_2025.07.04.663229v1.60","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202002566R"},{"key":"2025071101101463000_2025.07.04.663229v1.61","doi-asserted-by":"publisher","DOI":"10.1038\/s41577021-00563-6"},{"key":"2025071101101463000_2025.07.04.663229v1.62","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13993-7"},{"key":"2025071101101463000_2025.07.04.663229v1.63","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00658"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.07.04.663229","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:05:22Z","timestamp":1768467922000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.07.04.663229"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,8]]},"references-count":63,"URL":"https:\/\/doi.org\/10.1101\/2025.07.04.663229","relation":{},"subject":[],"published":{"date-parts":[[2025,7,8]]},"subtype":"preprint"}}