# Lymph Node Extracellular Matrix in Antigen Presentation and Immune Regulation > **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $502,859 ## Abstract PROJECT SUMMARY Type 1 diabetes (T1D) is an autoimmune disease associated with T-cell mediated destruction of insulin- producing β-cells. Prediabetic individuals typically lose tolerance first to insulin followed by other islet auto- antigens. This repeated, sequential loss of tolerance suggests that local antigenic responses may be skewed in T1D in ways that contribute to the loss of tolerance. We recently identified characteristic changes in the pancreatic lymph nodes (PLN) of individuals with T1D. Specifically, hyaluronan (HA), an extracellular matrix polymer, is abundant within the inter-follicular regions of PLN – the tissue sites where T-cell responses to self-antigens are primed – of cadaveric donors with T1D. Intrigued by these exciting results, we investigated the possibility that HA may play a role in loss of immune tolerance by potentiating the immune synapse between dendritic cells (DC) and T-cells. We find that activated, mature DC generate a “coat” of HA in association with hyaluronan synthase 3 (HAS3) that modulates antigen presentation, enhancing T-cell activation and proliferation in response to otherwise weak antigenic signals. Conversely, treatments that clear HA or disrupt its binding to CD44 (hyaluronidase, CD44 blocking antibodies, or 4-methylumbelliferone (4-MU), an HA synthesis inhibitor), reduce the efficiency of antigen presentation and promote peripheral FoxP3+ regulatory T-cells (Treg) induction. These data suggest a model whereby interactions between HA surrounding the DC and CD44 on T-cells stabilize the immune synapse. This stabilization, in turn, increases the effective affinity of TCR-MHC interactions, increasing positive selection of otherwise low affinity, autoreactive T-cells. This hypothesis, if true, represents a novel mechanism of co-stimulation of T-cells that contributes to the loss of immune tolerance in T1D. It may be possible to target HA therapeutically to promote tolerance. We recently reported that treatment with oral 4-MU prevented T1D and promoted Foxp3+ Treg expansion in multiple mouse models of T1D. These results are particularly exciting because 4-MU is already an approved drug, currently used for a different indication in children and adults. It may be possible to repurpose 4-MU to prevent T1D in at-risk subjects. However, it is essential that we first establish how HA promotes autoimmunity. We hypothesize that pericellular HA surrounding DC contributes to priming of autoreactive T-cells in T1D. To test this hypothesis, in Aim 1, we will determine how pericellular HA on DC impacts immune synapse formation with T-cells. In Aim 2, we will elucidate how pericellular HA on DC contributes to the loss of tolerance in autoimmune diabetes. Finally, in Aim 3, we will determine whether the appearance of HA within PLN coincides with the loss of tolerance in human prediabetes and the role of DC pericellular HA in mediating T-cell responses. Together, these studies will yield novel insights into the ... ## Key facts - **NIH application ID:** 9995461 - **Project number:** 5R01DK096087-09 - **Recipient organization:** STANFORD UNIVERSITY - **Principal Investigator:** Paul L Bollyky - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $502,859 - **Award type:** 5 - **Project period:** 2012-09-01 → 2022-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9995461 ## Citation > US National Institutes of Health, RePORTER application 9995461, Lymph Node Extracellular Matrix in Antigen Presentation and Immune Regulation (5R01DK096087-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9995461. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*