Profound Treg perturbations correlate with COVID-19 severity

Galván-Peña, Silvia; Leon, Juliette; Chowdhary, Kaitavjeet; Michelson, Daniel A.; Vijaykumar, Brinda; Yang, Liang; Magnuson, Angela M.; Chen, Felicia; Manickas-Hill, Zachary; Piechocka-Trocha, Alicja; Worrall, Daniel P.; Hall, Kathryn E.; Ghebremichael, Musie; Walker, Bruce D.; Li, Jonathan Z.; Yu, Xu G.; Mathis, Diane; Benoist, Christophe

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.