PhD Candidate Stanford University Stanford, California, United States
Introduction/Rationale: CD4+Foxp3+ regulatory T (Treg) cells maintain immune homeostasis by promoting protective responses, while limiting excessive inflammation. In severe COVID-19, this balance is disrupted, leading to pathologic inflammatory responses. Immunosuppressed individuals, such as solid organ transplant recipients, are at an increased risk for severe COVID-19, yet how immunosuppressive medications affect Treg cell function and inflammatory responses during SARS-CoV-2 infection remains unclear.
Methods: Using single-cell RNA sequencing, mass cytometry, and plasma proteomics, we compared peripheral immune responses in uninfected immunocompetent individuals, uninfected heart transplant recipients, and SARS-CoV-2-infected immunocompetent and immunosuppressed individuals. To mechanistically evaluate how immunosuppressive medications affect the regulatory function of Treg cells, primary human Treg cells treated with a calcineurin inhibitor, the most commonly used drug to maintain immunosuppression following solid organ transplantation, and exposed to proinflammatory cytokines elevated in severe SARS-CoV-2 infection, were profiled by flow cytometry and bulk RNA sequencing.
Results: We observed heightened peripheral immune activation and reduced Treg cell activation in both uninfected and infected immunosuppressed individuals compared to immunocompetent controls. In vitro treatment of primary human Treg cells with a calcineurin inhibitor impaired Treg cell response to inflammatory cytokines with reduced CD25 and TGF-β protein expression and broad transcriptomics perturbations demonstrating reduced suppressive function, independently of Foxp3 expression, which remain unchanged.
Conclusion: These findings suggest that calcineurin inhibitors contribute to dysregulated inflammatory responses in COVID-19 patients by compromising Treg cell function, providing insights that may inform therapeutic strategies for managing viral infections in immunocompromised populations.
