Dysregulated regulatory T cell response in immunosuppressed individuals is associated with increased inflammation in COVID-19 breakthrough infections 2587

Abstract Description Regulating the immune balance is important for launching protective immune responses, while curtailing pathologic responses. Regulatory T cells (Tregs) and immunosuppressants play key roles in this balance. This immune balance goes awry in severe COVID-19 marked by dysfunctional inflammatory responses. In immunosuppressed individuals, who are at an increased risk for severe COVID-19, the impact of immunosuppressants on Tregs and inflammatory responses in breakthrough infections remain unclear. Using single-cell RNA sequencing, mass cytometry, and plasma proteomics, we analyzed peripheral immune responses in uninfected immunocompetent individuals, uninfected heart transplant recipients, and both immunocompetent and immunosuppressed individuals with breakthrough COVID-19 infections. Unexpectedly, uninfected heart transplant recipients exhibited higher activation and pro-inflammatory states in key immune cells (CD4+ and CD8+ T cells, B cells, and CD14+ monocytes) and elevated plasma inflammatory markers (CXCL10, IFNγ, TNF, CCL3, CCL4, and MCP-1) compared to immunocompetent counterparts. This elevated inflammatory state may be partially attributed to dysregulated Treg activity and TGFβ signaling in heart transplants. We further discovered heightened peripheral immune activation and reduced Treg activation in immunosuppressed individuals with breakthrough infections, underscoring the impact of immunosuppressants on immune balance in COVID-19. Funding Sources Supported by NIH 5T32AI007290-37, F31AI179125, T32AI007502, 5T32HL129970, the Bill and Melinda Gates Foundation OPP113682, K23 HL124663, Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease 1016687, gift from the Quattrone Family, U19AI057229 – 17W1 COVID SUPP #2, Chan Zuckerberg Biohub Investigator Program, the Mercatus Center Topic Categories Immune Mechanisms of Human Disease (HUM)