期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2111315118
关键词
COVID-19; Tregs; tumor Tregs; FoxP3
资金
- Massachusetts Consortium for Pathogen Readiness (MassCPR) [R01 AI150686]
- JPB Foundation
- Mark and Lisa Schwartz Foundation
- Ragon Institute of MGH, Massachusetts Institute of Technology, and Harvard
- European Molecular Biology Organization [ALTF 547-2019]
- INSERM Poste d'Accueil
- National Institute of General Medical Sciences [T32GM007753]
- Harvard Stem Cell Institute MD/PhD Training Fellowship
- NIH/National Institute of Allergy and Infectious Diseases [P30-AI 060354]
- Arthur Sachs scholarship
- [R24 AI072073]
Severe COVID-19 is characterized by an uncontrolled inflammatory response, potentially linked to dysregulation in T regulatory cells (Treg) which may suppress antiviral T cell responses and have a direct proinflammatory role.
The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlating with poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19-linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.
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