Identifying mechanisms of TFH/germinal center b cell pathogenicity in type 1 diabetes

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Vanderbilt University $140,644 on December 13, 2025, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to identify mechanisms of T follicular helper and germinal center B cell pathogenicity in type 1 diabetes.

The research examines how T follicular helper cells and germinal center B cells interact to drive autoimmune destruction of pancreatic beta cells in type 1 diabetes. The project investigates T cell-B cell interactions that expand pathogenic responses and explores how anti-insulin B cells depend on germinal center T follicular helper cell interactions to license proinflammatory T cell subsets. The research employs newly developed non-obese diabetic mouse models, including genetic deletion of SLAM-associated protein and BCL6 models, to dissect the T follicular helper and germinal center B cell axis and test hypotheses about the molecular control of germinal center B cell and germinal center T follicular helper differentiation.

Work is performed in Nashville, Tennessee. The performance period extends through June 30, 2029. The award supports basic research addressing gaps in understanding type 1 diabetes pathogenesis with potential to improve the precision of T cell-B cell interaction-targeting immunotherapies and reduce heterogeneity in individual treatment responses.

Abstract

In type 1 diabetes (T1D), b lymphocytes present islet autoantigens to t cells, driving autoimmune destruction of pancreatic beta cells. Clinical trials targeting these t cell-b cell interactions have shown relative success, highlighting the importance of understanding pathogenic t-b interactions more precisely. The immediate challenges of these immunotherapies include a delay of T1D rather than durable protection, heterogeneity in individual responses, and undesirably broad immunosuppression. A major GAP in knowledge of T1D pathogenesis is how t cells interact with b lymphocytes to expand and acquire pathologic functional potential. T follicular helper (TFH)-like populations are increased in the peripheral blood of T1D individuals and high- affinity islet autoantibodies predict disease, pointing to a key role for germinal center (GC) TFH cell/GC b cell responses in T1D. In non-obese diabetic (NOD) mice, TFH cells can transfer diabetes. Work from our lab and others show that anti-insulin b cells can spontaneously adopt a GC phenotype, and that they can drive anti- insulin t cells to differentiate into TFH cells. Conversely, pathogenic anti-insulin t cell clones drive anti-insulin b cells to become GC b cells and produce insulin autoantibodies. Our recently published work demonstrated that CD4-driven expression of BCL6, which controls GC b cell and GC TFH differentiation, is required for T1D. Therefore, i hypothesize that T1D anti-insulin b cells depend on interactions with GC TFH cells to license the proinflammatory subsets of t cells that drives T1D pathogenesis. To test this hypothesis, we developed several new NOD models that allow dissection of the TFH/GC b cell axis. These include 1) a model in which genetic deletion of slam-associated protein (SAP) enables contrast between benign (SAP-/-) VS. Pathogenic (SAP+) TFH cells, 2) BCL6FL/FL models, and 3) anti-insulin BCR and TCR transgenic mice with which we can separate autoreactive b and t cell expansion from their acquisition of effector functions, and how this process is impacted by loss of the key GC proteins, BCL6 and SAP. In aim 1, i will determine the need for anti-insulin b cell engagement with TFH cells in supporting lymphocytic invasion of islets and diabetes development. In aim 2, i will dissect the pathogenic VS. Benign TFH phenotypic, metabolic, and transcriptomic changes in driving t cell functional changes in T1D. In aim 3, i will characterize known and novel subsets of circulating TFH-like cells elevated in pbmcs isolated from pre-symptomatic T1D individuals as they progress to diabetes onset. These experiments will identify key features of pathogenic TFH cells in both mouse and human cells and will provide insight into the molecular control of pathogenic t/b lymphocyte interactions. Studies using mouse models will link pathogenic immune infiltration of beta cells with changes that are observable in the peripheral blood, as this is a practical biospecimen for clinical evaluation of progression in pre-symptomatic T1D individuals, and immunotherapy response. This work thus holds potential to uncover novel immunologic biomarkers and immunotherapeutic targets to delay or prevent beta cell destruction in T1D.