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Coeliac disease (CeD) is an autoimmune disorder with well\u2010defined genetic risk and immune dysregulation triggered by dietary gluten. However, how genetic risk translates into cell\u2010intrinsic functional variation, particularly within the na\u00efve T\u2010cell compartment, remains poorly defined. Here, we developed the\n                    <jats:italic>T\u00a0cell momentum assay<\/jats:italic>\n                    , a quantitative functional profiling platform combining standardized T\u2010cell activation with defined stimulus withdrawal to measure proliferation, survival and activation dynamics over time. Integrated with the Cyton2 mathematical model, this approach infers cellular fate programs from population\u2010level dynamics, enabling high\u2010resolution analysis of intrinsic T\u2010cell behavior. Applying this assay to na\u00efve T\u00a0cells from individuals with CeD and healthy donors (HDs), we identified disease\u2010associated abnormalities predominantly in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u00a0cells, including hypoproliferation, reduced IL\u20102 secretion, impaired survival and delayed downregulation of CD69, indicating prolonged activation and impaired feedback regulation. Distinct early alterations in CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u00a0cells were also observed. These abnormalities were present in both newly diagnosed individuals and those on a gluten\u2010free diet, supporting a cell\u2010intrinsic phenotype not solely attributable to active inflammation and is consistent with altered baseline immune function. Together, our findings reveal previously unrecognized alterations in na\u00efve T\u2010cell programming in CeD, linking inherited immune variation to functional dysregulation beyond antigen\u2010specific responses. More broadly, the momentum assay offers a scalable, model\u2010informed framework to detect subtle early T\u00a0cell dysregulation and functionally stratify immune variation across autoimmune diseases.\n                  <\/jats:p>","DOI":"10.1111\/imcb.70132","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T06:10:33Z","timestamp":1779084633000},"page":"613-630","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Functional immune profiling reveals\n                    <scp>CD4<\/scp>\n                    <sup>+<\/sup>\n                    T\u00a0cell dysregulation in coeliac disease"],"prefix":"10.1111","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5234-0259","authenticated-orcid":false,"given":"Anthony J","family":"Farchione","sequence":"first","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"},{"name":"Department of Medical Biology University of Melbourne  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3004-6152","authenticated-orcid":false,"given":"HoChan","family":"Cheon","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Vremec","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julika","family":"Neumann","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwenny M","family":"Verstappen","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4923-0678","authenticated-orcid":false,"given":"Melinda Y","family":"Hardy","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"},{"name":"Department of Medical Biology University of Melbourne  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai B","family":"Margetts","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3522-4533","authenticated-orcid":false,"given":"Lauren J","family":"Howson","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"},{"name":"Department of Medical Biology University of Melbourne  Parkville VIC Australia"},{"name":"Department of Clinical Immunology &amp; Allergy The Royal Melbourne Hospital  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee M","family":"Henneken","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"},{"name":"Department of Gastroenterology The Royal Melbourne Hospital  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen","family":"Forde","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7687-9654","authenticated-orcid":false,"given":"Jason A","family":"Tye\u2010Din","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"},{"name":"Department of Medical Biology University of Melbourne  Parkville VIC Australia"},{"name":"Department of Gastroenterology The Royal Melbourne Hospital  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9524-2835","authenticated-orcid":false,"given":"Susanne","family":"Heinzel","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"},{"name":"Department of Medical Biology University of Melbourne  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip D","family":"Hodgkin","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"},{"name":"Department of Medical Biology University of Melbourne  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4697-7410","authenticated-orcid":false,"given":"Vanessa L","family":"Bryant","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville VIC Australia"},{"name":"Department of Medical Biology University of Melbourne  Parkville VIC Australia"},{"name":"Department of Clinical Immunology &amp; 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