Targeting Stem-like Progenitor CD8 T cells to Halt Autoimmune Attack in Hashimoto’s Thyroiditis

About This Grant

Project Summary Hashimoto’s Thyroiditis (HT) is a prevalent autoimmune disease affecting 15% of the population and characterized by chronic autoimmune attack on thyroid follicular cells. Over time, this persistent autoimmune attack results in thyroid gland failure and the requirement for lifelong hormone replacement, a hallmark shared with other chronic autoimmune diseases such as Type 1 Diabetes Mellitus (T1DM) and Addison’s Disease. Despite its prevalence, the mechanisms driving the unrelenting autoimmune attack in HT remain poorly understood. Identifying factors underlying the persistent autoimmune response, may identify new therapeutic targets to halt disease progression in HT and similar chronic autoimmune disorders. We have identified a population of TCF7+ stem-like progenitor CD8 T cells within the thyroid tissue of HT patients, analogous to those seen in chronic viral infections and Type 1 Diabetes, that sustain autoimmune attack by replenishing the pool of terminally differentiated cytotoxic effectors. Using single cell RNAseq and TCRseq of human thyroid specimens from individuals with HT, our preliminary data further demonstrate the transcriptional transition and clonal expansion of TCF7+ progenitor CD8 T cell to effectors with killing ability within the thyroid. In addition, our preliminary data suggest that tertiary lymphoid structures (TLSs), organized collection of immune cells within the thyroid, provide a microenvironment that promotes autoimmunity, driven in part by CD4 T follicular helper (Tfh) cells and IL-21, a cytokine implicated in CD8 T cell differentiation. Using a mouse model of HT, we demonstrate that IL-21R deletion protects against thyroid autoimmunity, suggesting that TLS-associated factors may drive the conversion of progenitor CD8 T cells into cytotoxic effectors. Thus, our overarching hypothesis is that TCF7+ CD8 T progenitor cells sustain autoimmune persistence in HT, while TLS- associated signals promote their differentiation into cytotoxic effectors, perpetuating disease progression. In Aim 1, we will define the role of TCF7 in maintaining stem-like CD8 T cells by genetically deleting TCF7 in an HT mouse model and using WNT pathway agonists to assess its regulatory function. In Aim 2, we will investigate TLS-driven CD8 T cell conversion by assessing the deletion of CD4 Tfh cells and IL- 21 signaling in HT progression using mouse models. We will leverage spatial transcriptomics data previously collected by our lab from HT thyroid specimens, to determine how TLS localization influences CD8 T cell differentiation. These studies will uncover fundamental mechanisms of chronic autoimmunity in HT, providing potential therapeutic targets to disrupt persistent autoimmune attack and yielding broader insights into T cell– mediated autoimmune diseases.