Illuminating immune-epithelial cell interactions that drive autoimmunity

Rachelly Normand ^1,2,3,5 Michelle Rengarajan ^1,2,3,5 Benjamin Arnold ^1,2,3,6 Michael Calcaterra ⁴ Alice Tirard ^1,2,3,6 Sareh Parangi ⁴ Gilbert H. Daniels ¹ Andrew D. Luster ^1,2,7 Alexandra-Chloe Villani ^1,2,3,5,6 Hoang Tran

¹Department of Medicine, Massachusetts General Hospital, USA
²Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, USA
³Broad Institute, Massachusetts Institute of Technology and Harvard, USA
⁴Department of Surgery, Massachusetts General Hospital, USA
⁵Harvard Medical School, USA, USA
⁶Center for Cancer Research, Massachusetts General Hospital, USA
⁷Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, USA

Thyroid autoimmunity is the one of the most common organ-specific autoimmune disorders and is a powerful model to study the break of immune tolerance and progression of disease in situ. We generated an unprecedented single cell atlas of human thyroid samples comprising of 375,337 cells from patients with Hashimoto’s thyroiditis (n=8), Graves’ disease (n=9) and control patients (n=6). This atlas was paired with T- and B- cell receptor repertoires and measurements of 204 surface proteins (CITE-seq). We profiled cell states at a resolution not yet described before for the thyroid gland, comprising of 64 immune cell states and 25 stromal and epithelial cell states. We then studied how the abundances of and interactions between these cell states change with the infiltration of immune cells into the glad during autoimmunity. We focused on an inflammatory epithelial subset that expresses MHC-II machinery, interferon stimulating genes and the checkpoint protein PD-L1. In addition, we found an inflammatory fibroblast population resembling a previously reported population playing a role in tertiary lymphoid structures in other tissues. We identified cell-cell interactions that are distinct in autoimmune setting and may contribute to disease progression and gland destruction. Studying two different thyroid autoimmunity disorders provides a unique opportunity to study the tissue at variable levels of immune cell infiltration and decipher the tissue response to autoimmunity.