Profound Treg perturbations correlate with COVID-19 severity
Silvia Galván-Peña, Juliette Léon, Kaitavjeet Chowdhary, Daniel A. Michelson, Brinda Vijaykumar, Liang Yang, Angela M. Magnuson, Felicia Chen, Zachary Manickas-Hill, Alicja Piechocka‐Trocha, Daniel Worrall, Kathryn Hall, Musie Ghebremichael, Bruce D. Walker, Jonathan Z. Li, Xu G. Yu, MGH COVID-19 Collection & Processing Team, Diane Mathis, Christophe Benoıst, Kendall M. Lavin-Parsons, Blair A. Parry, Brendan M. Lilley, Carl L. Lodenstein, Brenna McKaig, Nicole C. Charland, Hargun K. Khanna, Justin Margolin, Anna Gonye, Irena Gushterova, Tom Lasalle, Nihaarika Sharma, Brian C. Russo, Maricarmen Rojas-López, Moshe Sade-Feldman, Kasidet Manakongtreecheep, Jessica Tantivit, Molly Thomas
Abstract
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.