Patients with Covid-19 induced atypical thyroiditis have thyroid-resident memory T-cells specific for SARS-CoV-2

Ilaria Muller; Ylenia Silvestri; Francesca Clemente; Sara Maioli; Elena Carelli; Giorgia Moschetti; Alejandro Espadas; Feo Tullia De; Giovanna Mantovani; Maura Arosio; Mauro Bombaci; Elisa Pesce; Renata Grifantini; Sergio Abrignani; Mario Salvi; Jens Geginat

doi:10.1530/endoabs.90.P213

Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic disease (Covid-19) is associated with the onset of thyroid dysfunction via multiple mechanisms. Patients hospitalised for severe Covid-19 disease may develop painless atypical thyroiditis coexisting with non-thyroidal illness syndrome, which determines transient thyrotoxicosis with quick restoration of euthyroidism during the following weeks. However signs of thyroiditis at ultrasound and scintigraphy scans may persist up to one year. The SARS-CoV-2 immune responses play a key role in inducing secondary thyroid dysfunction, but little is known about anti-viral immune responses in the thyroid gland.

Methods: We analysed T-cell responses in 7 patients with severe Covid-19 disease developing atypical thyroiditis (COV-A-SAT). Paired blood and ultrasound-guided thyroid fine-needle aspiration (US-FNA) samples were obtained after 4 and 8 months following SARS-CoV-2 infection. Extracted lymphocytes were immunophenotyped by flow cytometry and stimulated with SARS-CoV-2 peptides. HLA-matched MHC I and II dextramers specific for SARS-CoV-2 peptides were also used to identify SARS-CoV-2-specific T-cells. The presence of intra-thyroid SARS-CoV-2 RNA on thyroid US-FNA samples was tested by real-time reverse transcriptase polymerase chain reaction 4 months post-infection.

Results: No intra-thyroid SARS-CoV-2 RNA was found 4 months post-infection. Despite the apparent viral clearing, COV-A-SAT patients still showed increased systemic T-cell activation as well as cytotoxic and Th1 effector cells, which returned to normal levels 8 months post-infection. Moreover, anti-SARS-COV2-specific CD4+ and CD8+ T-cell responses were readily detectable in peripheral blood 4 months post-infection, but were hardly detectable after 8 months. Unbiased bioinformatic analysis of T-cells in the thyroid gland and in peripheral blood unveiled unique T-cell clusters, in particular CD103+CD69+ tissue-resident memory cells (TRM) in the thyroid, and identified CXCR3+T-cells as their putative precursors in the blood. Importantly, SARS-COV2-specific T-cells were enriched in the thyroid gland, and acquired a TRM phenotype in particular 8 months post-infection.

Conclusions: These findings suggest that atypical thyroiditis developed by patients with severe Covid-19 is characterised by a prolonged, yet largely transient, systemic anti-viral effector T-cell response that results in the generation of long-lived tissue-resident memory cells in the thyroid. This local immune response may in part explain the persistence of signs of thyroiditis at thyroid ultrasound and scintigraphy scans up to one year following infection, despite the presence of normal thyroid function. Long-term clinical consequences are unknown.

Endocrine Abstracts

P213