# Mechanisms of T cell persistence during chronic autoimmunity > **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $668,683 ## Abstract PROJECT SUMMARY/ABSTRACT Chronic stimulation depletes memory T cell potential and leads to exhaustion. However, self-reactive autoimmune T cell responses persist and maintain function during chronic autoimmunity. The mechanisms behind persistence of autoimmune T cells, including resistance to regulatory mechanisms such as deletion and exhaustion, are not fully resolved and present a critical problem to our understanding and treatment of chronic autoimmunity. Importantly, increases in T cell exhaustion markers are correlated with autoimmune remission and positive responses to anti-CD3 therapy in type 1 diabetes (T1D), suggesting exhaustion to be an important regulatory mechanism in autoimmunity. Our intriguing new data show that a continuous influx of T cells from the periphery is necessary to maintain autoimmune T cell numbers in the pancreatic tissue during autoimmune diabetes, suggesting limitations in the ability of T cells to persist and self-renew at the tissue site. We have identified distinct CD4 T cell beta cell antigen populations infiltrating pancreatic islets in NOD mice. These populations are distinguished based on TCR affinity, level of stemness, differentiation, and effector function. Low affinity T cells are generally associated with a less differentiated phenotype, and preferentially form memory T cells. Low affinity T cells could be a critical reservoir for autoimmune T cell persistence. Whether low affinity T cells are differentially susceptible to regulatory mechanisms in autoimmunity is unknown. In this proposal we will interrogate autoimmune T cell capacity for stemness vs. exhaustion in the context of TCR affinity for self-antigen. We will assess the contribution of resident vs recruited cells to the tissue-infiltrating pathogenic population. We will determine whether high and low affinity T cells depend on the same mechanisms for survival and persistence during chronic stimulation. In combination, the Aims address the over-arching hypothesis that TCR affinity determines T cell persistence and avoidance of tolerance to chronic stimulation by pancreatic antigen. ## Key facts - **NIH application ID:** 10803516 - **Project number:** 1R01AI175494-01A1 - **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH - **Principal Investigator:** Maria Bettini - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $668,683 - **Award type:** 1 - **Project period:** 2023-12-01 → 2028-10-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10803516 ## Citation > US National Institutes of Health, RePORTER application 10803516, Mechanisms of T cell persistence during chronic autoimmunity (1R01AI175494-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10803516. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*