Profound Treg perturbations correlate with COVID-19 severity.
Silvia Galván-Peña, Juliette Leon, Kaitavjeet Chowdhary, Daniel A Michelson, Brinda Vijaykumar, Liang Yang, Angela M Magnuson, Felicia Chen, Zachary Manickas-Hill, Alicja Piechocka-Trocha, Daniel P Worrall, Kathryn E Hall, Musie Ghebremichael, Bruce D Walker, Jonathan Z Li, Xu G Yu, MGH COVID-19 Collection & Processing Team, Diane Mathis, Christophe Benoist
Author Information
Silvia Galván-Peña: Department of Immunology, Harvard Medical School, Boston, MA 02115.
Juliette Leon: Department of Immunology, Harvard Medical School, Boston, MA 02115.
Kaitavjeet Chowdhary: Department of Immunology, Harvard Medical School, Boston, MA 02115.
Daniel A Michelson: Department of Immunology, Harvard Medical School, Boston, MA 02115.
Brinda Vijaykumar: Department of Immunology, Harvard Medical School, Boston, MA 02115.
Liang Yang: Department of Immunology, Harvard Medical School, Boston, MA 02115.
Angela M Magnuson: Department of Immunology, Harvard Medical School, Boston, MA 02115.
Felicia Chen: Department of Immunology, Harvard Medical School, Boston, MA 02115.
Zachary Manickas-Hill: Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115.
Alicja Piechocka-Trocha: Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115.
Daniel P Worrall: Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115.
Kathryn E Hall: Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115.
Musie Ghebremichael: Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115.
Bruce D Walker: Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115. ORCID
Jonathan Z Li: Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115. ORCID
Xu G Yu: Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115.
Diane Mathis: Department of Immunology, Harvard Medical School, Boston, MA 02115.
Christophe Benoist: Department of Immunology, Harvard Medical School, Boston, MA 02115; cbdm@hms.harvard.edu.
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.
