W195 - Modeling the Effect of Immune Cell Infiltration on Tissue Function Reveals Cellular Rewiring Driving Human Thyroid Autoimmunity

Michelle Rengarajan – Massachusetts General Hospital; Hoang Tran – Massachusetts General Hospital; Benjamin Arnold – Massachusetts General Hospital; Michael Calcaterra – Massachusetts General Hospital; Sareh Parangi – Massachusetts General Hospital; Gilbert Daniels – Massachusetts General Hospital; Andrew Luster – Massachusetts General Hospital; Alexandra-Chloe Villani – Massachusetts General Hospital

Abstract Text: Thyroid autoimmunity is the one of the most common autoimmune disorders, in which the gland can become totally dysfunctional due to infiltration of immune cells. Yet, we currently lack a comprehensive understanding of the underlying processes that lead to functional impairment. Here we leveraged inter-patient variability to investigate how the cellular ecosystem changes during thyroid autoimmunity. We generated an unprecedented single-cell RNA sequencing atlas paired with T- and B- cell receptor (TCR/ BCR) repertoires and measurements of 204 surface proteins (CITE-seq) of human thyroid (375,337 cells) and paired blood (228,739 cells) generated from patients with Hashimoto’s thyroiditis (n=8), Graves’ disease (n=9) and control patients (n=6). Our analyses revealed a total of 89 immune, stromal, and epithelial cell states in the thyroid, including a unique epithelial cell population we termed “immuno-thyrocytes”. Immuno-thyrocytes upregulates immune-modulating and co-inhibitory genes and their frequency is correlative with gland functionality. We pinpointed specific CD8 T cell subsets that interact with immuno-thyrocytes. TCR clonal analysis revealed CD8 T cell subsets homing from the blood into the thyroid and defined a T cell differentiation trajectory for the most expanded tissue CD8 T cell clones. We identified additional critical players sustaining autoimmune disease, such as germinal center B cells, follicular helper CD4 T cells and inflammatory fibroblasts and modelled their co-dynamics. Finally, we propose a novel categorization of thyroid autoimmunity patients based on the level of immune cell infiltration rather than classifying them based on their autoimmune disease, which may prove to be relevant to other autoimmune disorders.