Functional immune profiling reveals <scp>CD4</scp> ⁺ T cell dysregulation in coeliac disease

Abstract T cells integrate signals from antigen and costimulatory receptors to calibrate response magnitude and quality, with genetically encoded programs shaping activation thresholds for immune tolerance and feedback regulation. Coeliac disease (CeD) is an autoimmune disorder with well‐defined genetic risk and immune dysregulation triggered by dietary gluten. However, how genetic risk translates into cell‐intrinsic functional variation, particularly within the naïve T‐cell compartment, remains poorly defined. Here, we developed the T cell momentum assay , a quantitative functional profiling platform combining standardized T‐cell 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‐level dynamics, enabling high‐resolution analysis of intrinsic T‐cell behavior. Applying this assay to naïve T cells from individuals with CeD and healthy donors (HDs), we identified disease‐associated abnormalities predominantly in CD4 + T cells, including hypoproliferation, reduced IL‐2 secretion, impaired survival and delayed downregulation of CD69, indicating prolonged activation and impaired feedback regulation. Distinct early alterations in CD8 + T cells were also observed. These abnormalities were present in both newly diagnosed individuals and those on a gluten‐free diet, supporting a cell‐intrinsic phenotype not solely attributable to active inflammation and is consistent with altered baseline immune function. Together, our findings reveal previously unrecognized alterations in naïve T‐cell programming in CeD, linking inherited immune variation to functional dysregulation beyond antigen‐specific responses. More broadly, the momentum assay offers a scalable, model‐informed framework to detect subtle early T cell dysregulation and functionally stratify immune variation across autoimmune diseases.