Thyroid hormone receptor α signaling shapes innate and adaptive immune responses during viral infection.

Objective: Thyroid hormones (TH) are well-known regulators of the immune system. However, the precise immunomodulatory mechanisms of TH action in immune cells remain elusive. In a previous study, an essential role of the TH receptor α (TRα) in regulatory T cell (Treg) immunity was demonstrated, affecting Treg activation at steady state. The present study therefore aimed to unravel the biological relevance of altered TRα action in protective immune responses during disease. Methods: To assess the role of TRα action in immune responses, especially T cell responses, during disease, different TRα signaling mouse models (TRαKO, complete lack of TRα signaling; TRαGS, lack of canonical signaling) were challenged with influenza virus A/PR8/34, and in-depth immune phenotyping was performed. Results: Upon influenza virus infection, TRαGS mice, which lack canonical TRα signaling, showed prolonged survival and reduced disease severity, correlating with enhanced anti-inflammatory Treg and decreased pro-inflammatory CD4 and CD8 T cell responses. The loss of TRα action in TRαKO mice was related to elevated viral titers upon influenza virus infection, which correlated with increased inflammatory monocyte responses early during infection. Conclusion: The present study demonstrates a complex role of TRα signaling in protective immune responses during disease, with distinct effects on innate and adaptive immune cells. By exploring the understudied link between the endocrine and immune systems, this study provides novel evidence for the role of TH as modulators of immunity.